Endocrinology and Neuroimmunology - Stress and Sleep Deprivation Studies

2011-12-10T10:40:00.000-08:00

THE BASICS:

-MY STUDY
-THE IMPACT OF SLEEP DEPRIVATION ON HORMONES AND METABOLISM
-TERMINOLOGY

Candida and Probiotics

2010-09-10T12:15:00.000-07:00

Candida and Probiotics

Probiotics provide Candida-inhibiting activities of commensal bacteria that reside in the alimentary and vaginal tracts of humans. Probiotic microbes not only suppress the growth of Candida spp in the alimentary tract and vagina, but they also inhibit the adherence of Candida spp to epithelial surfaces(11).

Lactobacilli and Bifidobacteria have the capacity to inhibit Candida spp.

Each strain can have a different effect. That is the reason, Custom Probiotics formulates and supplies single and multistrain highest potency and quality probiotic bacteria for maximum effectiveness. We perform rigorous independent lab testing to verify the bacterial count of every batch to guarantee the potency of our probiotic dietary supplements.

A variety of mechanisms have been evoked to explain the anti-Candida activity of the probiotics. Nutritional competition, blocking receptors to Candida spp., adhesions on epithelial cells, production of anti-Candida compounds, increasing intestinal peristalsis, increasing intestinal epithelial cell renewal rates, alteration of pH and the production of an anaerobic oxidation-reduction potential (C. albicans is an aerobic microbe) have all been proposed as mechanisms that probiotic bacteria use to inhibit pathogens on mucosal surfaces.
The ability of probiotic bacteria to stimulate innate and acquired immune systems in the host and activate phagocytic cells is also thought to play a role in the inhibition of Candida spp. It is very likely that because of the recognized complexity of the aerobic and anaerobic normal flora, all the above factors are involved in the suppression of Candida spp. on mucosal surfaces. As a result, the inhibition of Candida spp. by probiotic bacteria, in the alimentary and vaginal tracts, represents a key, first-line defense against mucosal and systemic candidiasis.
http://www.customprobiotics.com/candida.htm

Systemic bacterial invasion induced by sleep deprivation

2010-09-10T11:44:00.000-07:00

Systemic bacterial invasion induced by sleep deprivation

Am J Physiol Regul Integr Comp Physiol 278: R905-R916, 2000;

0363-6119/00 $5.00
Vol. 278, Issue 4, R905-R916, April 2000

Carol A. Everson1 and Linda A. Toth2

1 Department of Physiology, University of Tennessee College of Medicine and 2 Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis Tennessee 38163

Profound sleep disruption in humans is generally believed to cause health impairments.

Through comparative research, specific physical effects and underlying mechanisms altered by sleep deprivation are being elucidated.

Studies of sleep-deprived animals previously have shown a progressive, chronic negative energy balance and gradual deterioration of health, which culminate in fatal bloodstream infection without an infectious focus.

The present study investigated the conditions antecedent to advanced morbidity in sleep-deprived rats by determining the time course and distribution of live microorganisms in body tissues that are normally sterile.

The tissues cultured for microbial growth included the blood, four major organs, six regional lymph nodes, the intestine, and the skin.

The principal finding was early infection of the mesenteric lymph nodes by bacteria presumably translocated from the intestine and bacterial migration to and transient infection of extraintestinal sites.

Presence of pathogenic microorganisms and their toxins in tissues constitutes a septic burden and chronic antigenic challenge for the host.

Bacterial translocation and pathogenic sequelae provide mechanisms by which sleep deprivation appears to adversely affect health.

http://ajpregu.physiology.org/cgi/content/abstract/278/4/R905

Sleep Deprivation and Host Defense

Am J Physiol Regul Integr Comp Physiol 280: R602-R603, 2001;
0363-6119/01 $5.00
Vol. 280, Issue 2, R602-R603, February 2001

To the Editor: Rechtschaffen and Bergmann cite studies that they contend counter our suggestion that systemic bacterial invasion and antigenic challenge are a likely cause of physiological signs induced by sleep deprivation (5). A number of issues must be considered in the interpretation of those studies and the extent to which they are germane to the present study.
A 1989 publication by Benca and colleagues (2) reported the results of in vitro proliferation and antibody tests on spleen cells collected from rats late in the experimental period. The findings showed that as compared with the responses of yoked rats, about half of the sleep-deprived rats showed reduced cellular responsiveness and half showed greater responsiveness in both assays. Thus the effects were not consistent. Moreover, bacterial translocation is not dependent on impaired lymphoproliferation, and in vitro antibody production by B cells is not necessarily reflective of sepsis.
The report of an increased rate of regression of experimentally induced subcutaneous tumors in sleep-deprived versus yoked rats (4) is an intriguing finding, but this effect is nonspecific and could be related to metabolic rather than immunologic mechanisms. The report therefore did not influence how we interpreted our findings.
Impaired host defense, accompanied by systemic infections and the many physiological and metabolic changes associated with septic states, provides a plausible explanation for signs of sleep deprivation, including hypercatabolism, a well-known consequence of infectious disease states (1). We measured numbers of live bacteria and not the many intermediary physiological responses that would link the presence of bacteria to the development of other signs. Therefore, our study was not designed to reveal correlations that might establish relationships between bacterial invasion and the progressive development of other signs associated with chronic sleep deprivation.
In a study designed to show that elimination of aerobic bacteria does not markedly alter the physiological signs associated with chronic sleep deprivation, Bergmann and colleagues (3) administered an antibiotic cocktail to rats during the baseline period and the first 4 days of sleep deprivation.

Despite this prophylactic treatment, however, eight sleep-deprived or yoked rats were excluded from analysis due to positive bacterial cultures, suggesting that the antibiotic regimen was largely ineffective.

Data from the remaining four bacteria-negative sleep-deprived rats, combined with similar data from rats given the antibiotic cocktail late during the course of sleep deprivation, were the basis for the reported negative correlation.

An absence of positive cultures of aerobic bacteria in a subset of antibiotic-treated sleep-deprived rats does not negate the finding or the implications of positive cultures of pathogenic microorganisms in untreated or even treated sleep-deprived rats.

Furthermore, the absence of positive blood or tissue cultures in septicemic patients is a well-known clinical phenomenon and does not negate the state of sepsis.

Moreover, factors other than aerobic bacteria (e.g., endotoxins derived from gut contents or killed translocated bacteria) can cause similar metabolic derangements.

Our data indicate impaired host defense, evidenced by the presence of live bacteria in normally sterile tissues.

We hypothesize that physiological changes induced by sleep deprivation allow bacteria to leave the gut, evade antimicrobial systems, and cause transient infections and finally septicemia, which leads to the death of the animal.

We thus view the presence of bacteria as a sign of a more fundamental abnormality. Clinically significant bacterial translocation and posttranslocation survival of bacteria typically does not occur in the absence of local or systemic immune impairment.

http://ajpregu.physiology.org/cgi/content/full/280/2/R602

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Partial sleep deprivation compromises gastric mucosal integrity in rats

2010-09-10T10:56:00.000-07:00

Partial sleep deprivation compromises gastric mucosal integrity in rats

Copyright © 2005 Elsevier Inc. All rights reserved.

Jin Sheng Guoa, b, Jenny Fung Ling Chaua, Chi Hin Choa and Marcel Wing Leung Kooa, ,

aDepartment of Pharmacology, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China

bDivision of Digestive Diseases, Department of Internal Medicine, Zhong Shan Hospital, Fu Dan University, Shanghai, 200032, China

Received 27 June 2004; accepted 29 December 2004. Available online 3 February 2005.

Abstract

The gastric mucosa is most susceptible to stress that has been shown to induce mucosal damage in humans and animals.

This study aims to explore the underlying mechanisms of partial sleep deprivation, as a source of psychophysiological stress, on gastric functions and its effect on mucosal integrity.

Sprague-Dawley rats were partially sleep deprived (PSD) for 7 or 14 days by housing inside slowly rotating drums.

Gastric tissues and plasma were sampled at the end of the sleep deprivation periods and mucosal lesion scores were evaluated.

Morphological examination was performed after Hematoxylin and Eosin staining.

Plasma levels of noradrenaline, adrenaline, gastrin, histamine and somatostatin were determined with enzyme immunoassays.

Gastric acidity was measured with acid-base titration in pylorus ligated rats.

Gastric mucosal blood flow was evaluated with Laser Doppler Flowmetry.

It was found that gastric lesions were induced in about 30%–50% of the PSD rats.

Gastric acidity as well as plasma levels of noradrenaline, gastrin and histamine were elevated.

Gastric mucosal blood flow and plasma somatostatin level were on the contrary reduced, especially in rats with PSD for 14 days.

It is concluded that partial sleep deprivation compromises gastric mucosal integrity by increasing gastric acidity, plasma levels of noradrenaline, gastrin, histamine, and decreasing gastric mucosal blood flow.

These results provided experimental evidence on the gastric damaging effects of PSD and it could be one of the risk factors contributing to gastric ulcer formation.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T99-4FD9T34-2&_user=10&_coverDate=05%2F27%2F2005&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1457174832&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=f9811966dbe182c07f98894c3124fd8b&searchtype=a

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Corticotropin-releasing hormone (CRH) downregulates interleukin-18 expression in human HaCaT keratinocytes

2010-08-16T11:55:00.000-07:00

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Corticotropin-releasing hormone (CRH) downregulates interleukin-18 expression in human HaCaT keratinocytes by activation of p38 mitogen-activated protein kinase (MAPK) pathway.

Park HJ, Kim HJ, Lee JH, Lee JY, Cho BK, Kang JS, Kang H, Yang Y, Cho DH.
Department of Dermatology, St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

It is generally accepted that corticotropin-releasing hormone (CRH) acts as the main coordinator of the central response to stress.

Stress or an abnormal response to stressors has been found to modify the evolution of skin disorders, including psoriasis and atopic dermatitis.

Nevertheless, the specific pathogenic role of stress remains unknown in skin diseases.

Interleukin (IL)-18, a member of the IL-1 family, is a key mediator of peripheral inflammation and host defense responses, and is secreted by human keratinocytes.

Here, we investigated the regulatory effect of CRH on expression of IL-18 in skin keratinocytes.

Exposure of HaCaT cells to CRH resulted in a reduction of IL-18 mRNA transcripts and its production was in a concentration-dependent manner.

In order to investigate whether the mitogen-activated protein kinase (MAPK) signaling pathway is involved in the downregulation of IL-18 production, cells were pre-treated with SB203580, an inhibitor of p38 MAPK, prior to the addition of CRH.

This pre-treatment blocked the decrease in IL-18 production.

In addition, CRH treatment induced rapid phosphorylation of p38 MAPK. SB203580 were able to inhibit CRH-induced p38 MAPK phosphorylation.

CRH also inhibited production of IL-18 in human primary keratinocytes.

These results suggest that CRH regulates IL-18 production through the MAPK signaling pathway in human keratinocytes.

http://www.ncbi.nlm.nih.gov/pubmed/15816833

Stimulation of LH secretion in sheep by central administration of corticotrophin-releasing hormone

2010-05-14T14:22:00.000-07:00

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Journal of Reproduction and Fertility (1997) (1997) 111 249-257 DOI: 10.1530/jrf.0.1110249Copyright © 1997 Society for Reproduction and Fertility

Stimulation of LH secretion in sheep by central administration of corticotrophin-releasing hormone

A. Caraty, D. W. Miller, B. Delaleu and G. B. Martin

Corticotrophin-releasing hormone (CRH) has been proposed as a mediator of the antireproductive effects of stress through an action within the hypothalamus to inhibit GnRH secretion.

This hypothesis was tested in sheep by studying the responses to central administration of CRH in both sexes and in both seasons.

Sexually mature, Ile-de-France ewes and Romanov rams that had been gonadectomized and implanted with a permanent guide cannula into the third cerebral ventricle were used.

Ewes were studied in the presence and absence of exogenous oestradiol plus progesterone, in both the breeding and anoestrous seasons.

All rams were treated with testosterone and were studied only during the breeding season.

Each observation involved serial samples (every 10 min) of jugular blood for 5 h before (control) and 5 h after an intracerebroventricular (icv) injection of either saline (vehicle) or 5 nmoles CRH in 20 µl vehicle.

The saline injections did not affect any of the endocrine variables measured; however, CRH always increased cortisol concentrations in jugular plasma.

In the absence of treatment with replacement sex steroids, icv injection of CRH had no effect on pulsatile LH secretion in females either during the breeding season or during anoestrus.

However, LH pulse frequency and mean LH concentrations increased significantly on every occasion on which animals were treated with sex steroids.

Treatment with CRH also increased LH secretion in the testosterone-treated rams.

It is concluded that, contrary to the hypothesized role of CRH as an inhibitor of reproductive activity, this neuropeptide stimulates pulsatile LH (and thus GnRH) secretion, at least in this species.

The fact that gonadal steroids seem to be obligatory for the expression of this effect suggests that the protocols used in past studies need to be reassessed.

http://www.reproduction-online.org/cgi/content/abstract/111/2/249

Luteinizing hormone (LH, also known as lutropin[1]) is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation.

http://en.wikipedia.org/wiki/Luteinizing_hormone

Noradrenergic activity in rat brain during rapid eye movement sleep deprivation and rebound sleep

2009-12-21T16:18:00.000-08:00

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Am J Physiol Regul Integr Comp Physiol 268: R1456-R1463, 1995; 0363-6119/95 $5.00

AJP - Regulatory, Integrative and Comparative Physiology, Vol 268, Issue 6 1456-R1463, Copyright © 1995 by American Physiological Society

Noradrenergic activity in rat brain during rapid eye movement sleep deprivation and rebound sleep

T. Porkka-Heiskanen, S. E. Smith, T. Taira, J. H. Urban, J. E. Levine, F. W. Turek and D. Stenberg Department of Physiology, University of Helsinki, Finland.

Noradrenergic locus ceruleus neurons are most active during waking and least active during rapid eye movement (REM) sleep.

We expected REM sleep deprivation (REMSD) to increase norepinephrine utilization and activate the tyrosine hydroxylase (TH) gene critical for norepinephrine production.

Male Wistar rats were deprived of REM sleep with the platform method.

Rats were decapitated after 8, 24, or 72 h on small (REMSD) or large (control) platforms or after 8 or 24 h of rebound sleep after 72 h of the platform treatment.

During the first 24 h, norepinephrine concentration, measured by high-performance liquid chromatography/electrochemical detection, was lower in the neocortex, hippocampus, and posterior hypothalamus in REMSD rats than in large-platform controls.

After 72 h of REMSD, TH mRNA, measured by in situ hybridization, was increased in the locus ceruleus and norepinephrine concentrations were increased.

Polygraphy showed that small-platform treatment caused effective and selective REMSD.

Serum corticosterone measurement by radioimmunoassay indicated that the differences found in norepinephrine and TH mRNA were not due to differences in stress between the treatments.

The novel finding of sleep deprivation-specific increase in TH gene expression indicates an important mechanism of adjusting to sleep deprivation.

Norepinephrine
From Wikipedia, the free encyclopedia

Noradrenaline (BAN) (abbreviated NA or NAd) or norepinephrine (INN) (abbreviated norepi or NE) is a catecholamine with dual roles as a hormone and a neurotransmitter.[2]
As a stress hormone, norepinephrine affects parts of the brain where attention and responding actions are controlled. Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle.
However, when norepinephrine acts as a drug it will increase blood pressure by its prominent increasing effects on the vascular tone from α-adrenergic receptor activation. The resulting increase in vascular resistance triggers a compensatory reflex that overcomes its direct stimulatory effects on the heart, called the baroreceptor reflex, which results in a drop in heart rate called reflex bradycardia.
Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase.[3] It is released from the adrenal medulla into the blood as a hormone, and is also a neurotransmitter in the central nervous system and sympathetic nervous system where it is released from noradrenergic neurons. The actions of norepinephrine are carried out via the binding to adrenergic receptors.

Mechanism
Norepinephrine is synthesized from tyrosine as a precursor, and packed into synaptic vesicles. It performs its action by being released into the synaptic cleft, where it acts on adrenergic receptors, followed by the signal termination, either by degradation of norepinephrine, or by uptake by surrounding cells.

http://en.wikipedia.org/wiki/Norepinephrine

Corticotropin-Releasing Hormone (CRH) Downregulates the Function of Its Receptor (CRF1)

2009-10-29T11:44:00.000-07:00

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Corticotropin-Releasing Hormone (CRH) Downregulates the Function of Its Receptor (CRF1) and Induces CRF1 Expression in Hippocampal and Cortical Regions of the Immature Rat Brain

Kristen L. Brunsona, Dimitri E. Grigoriadisb, Marge T. Lorangb and Tallie Z. Baramc, a
a Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, California, 92697

c Department of Pediatrics, University of California at Irvine, Irvine, California, 92697
b Neurocrine Biosciences Inc. La Jolla, California, 92121
Received 26 October 2001;
accepted 27 March 2002. ;

Available online 2 July 2002.

Abstract

In addition to regulating the neuroendocrine stress response, corticotropin-releasing hormone (CRH) has been implicated in both normal and pathological behavioral and cognitive responses to stress.

CRH-expressing cells and their target neurons possessing CRH receptors (CRF1 and CRF2) are distributed throughout the limbic system, but little is known about the regulation of limbic CRH receptor function and expression, including regulation by the peptide itself.

Because CRH is released from limbic neuronal terminals during stress, this regulation might play a crucial role in the mechanisms by which stress contributes to human neuropsychiatric conditions such as depression or posttraumatic stress disorder.

Therefore, these studies tested the hypothesis that CRH binding to CRF1 influenced the levels and mRNA expression of this receptor in stress-associated limbic regions of immature rat.

Binding capacities and mRNA levels of both CRF1 and CRF2 were determined at several time points after central CRH administration.

CRH downregulated CRF1 binding in frontal cortex significantly by 4 h.

This transient reduction (no longer evident at 8 h) was associated with rapid increase of CRF1 mRNA expression, persisting for >8 h.

Enhanced CRF1 expression—with a different time course—occurred also in hippocampal CA3, but not in CA1 or amygdala, CRF2 binding and mRNA levels were not altered by CRH administration.

To address the mechanisms by which CRH regulated CRF1, the specific contributions of ligand–receptor interactions and of the CRH-induced neuronal stimulation were examined.

Neuronal excitation without occupation of CRF1 induced by kainic acid, resulted in no change of CRF1 binding capacity, and in modest induction of CRF1 mRNA expression.

Furthermore, blocking the neuroexcitant effects of CRH (using pentobarbital) abolished the alterations in CRF1 binding and expression.

These results indicate that CRF1 regulation involves both occupancy of this receptor by its ligand, as well as “downstream” cellular activation and suggest that stress-induced perturbation of CRH–CRF1 signaling may contribute to abnormal neuronal communication after some stressful situations.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WFG-466CG3D-7&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1070019700&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=ccddf7fb2570ed531ae236ebf17a4ea0

CRH Enhances Retention of a Spatial Memory

2009-10-27T13:09:00.000-07:00

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Performing your original search, crh memory, in PubMed will retrieve 54 records.

Neurobiol Learn Mem. 2008 May;89(4):370-8. Epub 2007 Dec 20.

Post-training administration of corticotropin-releasing hormone (CRH) enhances retention of a spatial memory through a noradrenergic mechanism in male rats.

Row BW, Dohanich GP.
Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY 40202, USA.
Hormones released in response to stress play important roles in cognition. In the present study, the effects of the stress peptide, corticotropin-releasing hormone (CRH), on spatial reference memory were assessed following post-training administration. Adult Long-Evans male rats were trained for 6 days on a standard water maze task of reference memory in which animals must learn and remember the fixed location of a hidden, submerged platform. Each day, immediately following three training trials, rats received bilateral infusions of CRH into the lateral ventricles over a range of doses (0.1, 0.33, 1.0, 3.3 microg) or a vehicle solution. Post-training infusions of CRH improved retention as indicated by significantly shorter latencies and path lengths to locate the hidden platform on the first training (retention) trial of days 2 and 3. Additionally, post-training administration of CRH increased spatial bias during probe trials as measured by proximity to the platform location. CRH did not enhance performance on retention or probe trials when administered 2h after daily training indicating that CRH facilitated consolidation specifically. The effects of CRH were attenuated by intraventricular co-administration of the beta-adrenergic antagonist, propanolol, at bilateral doses that had no effect on retention alone (0.1, 1.0 microg). Results indicate that post-training administration of CRH enhanced spatial memory as measured in a water maze, and this effect was mediated, at least partly, by a noradrenergic mechanism.
PMID: 18086539 [PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms, Substances

http://www.ncbi.nlm.nih.gov/pubmed/18086539

Norepinephrine

From Wikipedia, the free encyclopedia

Noradrenaline (BAN) (abbreviated NA or NAd) or norepinephrine (INN) (abbreviated norepi or NE) is a catecholamine with dual roles as a hormone and a neurotransmitter.[2]

As a stress hormone, norepinephrine affects parts of the brain where attention and responding actions are controlled. Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle.
However, when norepinephrine acts as a drug it will increase blood pressure by its prominent increasing effects on the vascular tone from α-adrenergic receptor activation. The resulting increase in vascular resistance triggers a compensatory reflex that overcomes its direct stimulatory effects on the heart, called the baroreceptor reflex, which results in a drop in heart rate called reflex bradycardia.
Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase.[3] It is released from the adrenal medulla into the blood as a hormone, and is also a neurotransmitter in the central nervous system and sympathetic nervous system where it is released from noradrenergic neurons. The actions of norepinephrine are carried out via the binding to adrenergic receptors.

SEE MORE! at:

http://en.wikipedia.org/wiki/Norepinephrine

SEE ALSO:

Dopamine
http://en.wikipedia.org/wiki/Dopamine

Prolactin
http://en.wikipedia.org/wiki/Prolactin

Copyright © 1999 Elsevier Science Inc. All rights reserved.
Original Articles

Changes in hippocampal theta following intrahippocampal corticotropin-releasing hormone (CRH) infusions in the rat

Rudie Kortekaas , , a, Brenda Costalla and James W. Smythea
a Department of Pharmacology, University of Bradford, Bradford, UK

Received 7 October 1998;
revised 2 February 1999;
accepted 2 February 1999.
Available online 1 June 1999.

Abstract

Hippocampal theta activity is a large amplitude, sinusoidal wave that occurs during attentive immobility and exploratory behaviour in the rat, and it is thought to be involved in memory formation.

Recent reports suggest that corticotropin-releasing hormone (CRH) has pro-mnemonic effects in rodents.

(A mnemonic device (pronounced /nɨˈmɒnɨk/[1]) is a mind memory and/or learning aid. Commonly, mnemonics are verbal—such as a very short poem or a special word used to help a person remember something - wikipedia)

Because memory-enhancing substances/manipulations generally alter either theta frequencies or amplitudes, these variables were monitored in urethane-anaesthetised rats following intra-hippocampal infusions of CRH.

Adult male, Lister hooded rats were implanted with a hippocampal recording electrode and a guide cannula, both aimed at the dentate gyrus.

When CRH was infused into the hippocampus, the main change in the hippocampal EEG was a slow onset increase in the amplitude of spontaneous theta and, paradoxically, a significant decrease in the amount of time spent displaying theta.

These data suggest that CRH has the ability to modulate ongoing hippocampal theta, but, considering the slow effect, the involvement of hippocampal CRH receptors is suspect. Regardless of locus, the described electrophysiological changes suggest that hippocampal cholinergic systems may play a role in the memory-enhancing effects of CRH.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6SYT-3WKY1S9-6&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1066745569&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=ed79d8585decfce3507a3675c4a5f584

Involvement of the corticotropin-releasing hormone system in the pathogenesis of acne vulgaris

2009-10-27T12:47:00.000-07:00

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Involvement of the corticotropin-releasing hormone system in the pathogenesis of acne vulgaris.

Br J Dermatol. 2009 Feb;160(2):345-52. Epub 2008 Dec 10.
Ganceviciene R, Graziene V, Fimmel S, Zouboulis CC.

Centre of Dermatovenereology, Vilnius University Hospital, Santariskiu Klinikos, Vilnius, Lithuania.

Comment in:

Br J Dermatol. 2009 Feb;160(2):229-32.

BACKGROUND:

The sebaceous gland exhibits an independent peripheral endocrine function and expresses receptors for neuropeptides.

Previous reports have confirmed the presence of a complete corticotropin-releasing hormone (CRH) system in human sebocytes in vitro.

The capability of hypothalamic CRH to induce lipid synthesis, induce steroidogenesis and interact with testosterone and growth hormone implicates a possibility of its involvement in the clinical development of acne.

OBJECTIVES:

The purpose of the study was to detect expression changes of CRH/CRH binding protein (CRHBP)/CRH receptors (CRHRs) in acne-involved skin, especially in the sebaceous glands.

METHODS:

Expression of CRH/CRHBP/CRHRs was analysed by immunohistochemistry in biopsies from facial skin of 33 patients with acne, noninvolved thigh skin of the same patients and normal skin of eight age-matched healthy volunteers.

RESULTS:

Very strong positive reaction for CRH was observed in acne-involved skin in all types of sebaceous gland cells, irrespective of their differentiation stage, whereas in noninvolved and normal skin sebaceous glands exhibited a weaker CRH staining depending upon the differentiation stage of sebocytes.

The strongest reaction for CRHBP (binding protein) in acne-involved sebaceous glands was in differentiating sebocytes.

CRHR-1 and CRHR-2 exhibited the strongest expression in sweat glands and sebaceous glands, respectively.

CONCLUSIONS:

Expression of the complete CRH system is abundant in acne-involved skin, especially in the sebaceous glands, possibly activating pathways which affect immune and inflammatory processes leading to the development and stress-induced exacerbation of acne.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=19077080%5Buid%5D

CRH and GPI-anchored Gas families are FUNGAL ANTIGENS

2009-10-24T05:05:00.000-07:00

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2007: Arroyo Javier; Sarfati Jaqueline; Baixench Marie Thérése; Ragni Enrico; Guillén Marivi; Rodriguez-Peña José Manuel; Popolo Laura; Latgé Jean Paul

The GPI-anchored Gas and Crh families are fungal antigens

Yeast (Chichester, England) 2007;24(4):289-96.

The cell wall is the first interface between a fungus and its extracellular environment.

Glycosyltransferases involved in the formation and dynamic remodelling of the polysaccharide network of the cell wall have recently been identified.

The best characterized ones belong to the
Gas family, which elongates beta(1,3)-glucans, and to the
Crh family, which are involved in the cross-linking of chitin to beta(1,6)-glucan. (SEE BELOW ON THE LARGE)

All these proteins carry a glycosylphosphatidylinositol (GPI) anchor. (SEE BELOW ON THE LARGE)

In this work, we show that recombinant soluble forms of Gas1-5 and Crh1p from Saccharomyces cerevisiae and their orthologous proteins Gel1-Gel2 and Crf1 from Aspergillus fumigatus are specifically recognized by antibodies present in the sera of patients with Aspergillus or Candida infections.

Quantification of the antibody titres against recombinant Gas/Gel and Crh/Crf proteins separated aspergilloma and candidiasis patients from non-infected individuals.

Cross-reactivity was seen between the antibody response of patients with aspergillosis and candidiasis towards the Gas/Gel and Crh/Crf proteins.

These results suggest that GPI-anchored cross-linking enzymes are relevant immunologically reactive constituents of the cell wall that may play a role during human fungal infections.

http://www.biomedexperts.com/Abstract.bme/17397107/The_GPI-anchored_Gas_and_Crh_families_are_fungal_antigens

The Corticotropin-Releasing Hormone (CRH) family of peptides

The 41-amino acid sequence of CRH was first discovered in sheep by Vale et al. in 1981

http://en.wikipedia.org/wiki/Corticotropin-releasing_hormone

CRH is a 41-amino acid peptide that was first isolated from the sheep hypothalamus.

It has since been found in a large variety of species with a high degree of sequence identity, emphasizing the importance of this hormone.

The human CRH gene consists of two exons separated by an intron in its 5' untranslated region. The rat and ovine CRH genes have the same organization. While CRH accounts for a large part of the corticotropin-releasing activity of extracts in the hypothalamus, it does not account for all of it.

In fact there appears to be a wider family featuring structurally related peptides, including sauvagine in amphibia, urotensin I in teleost fish and urocortin in mammals.

Urocortin is localizaed in the rat midbrain region, testis, cardiac myocytes, thymus, spleen, kidney and human reproductive tissues.

CRH-like activity is widely distributed in:
-central nervous system,
-adrenals,
-lungs,
-liver,
-stomach,
-pancreas,
-small intestine and
-reproductive tissues and in a variety of
-human tumours.

The following systems are affected by CRH through extrapituitary mechanisms:
-cardiovascular regulation,
-respiration,
-appetite control,
-glucose metabolism,
-immune function, and
-cognitive and motor behaviour.

Moreover, immunoreactive CRH found in reproductive tissues can exert a number of effects. It can participate in intrauterine inflammatory processes of early pregnancy.

Recently, two new members of the CRH neuropeptide family have been cloned:
-stress-copin-related peptide (SRP)/urocortin II and
-stresscopin (SCP)/urocotrtin III.

SRP/ urocortin III mRNA expression have been detected in the gastrointestinal tract, muscle, adrenal gland and skin.

CRH Receptors

CRH Receptors belong to the class II superfamily of "brain-gut" neuropeptide receptors, which all contain 7 transmembrane helical domanins and share considerable sequence identity with one another.

Currently there are 2 known classes of CRH receptors, termed type 1 and type 2, that have been cloned from a number of vertebrate species and are encoded by separate genes.

CRH-R1 shares 70% identity with CRH-R2 and both receptors are present in structurally distinct isoforms.

The CRH-R1 gene expresses multiple subtypes, 1alpha-h, which are produced by differential exon splicing.

Each CRH-R1 variant has a defect in its expression, binding or signalling characteristics; for example, CRH-R1 beta contains a 29-amino-acid insertion in its first intracellular loop, allowing only weak coupling to the stimulatory G-protein.

The CRH-R2 gene expresses 3 known subtypes, 2alpha, 2beta and 2epsilon, that are produced by the use of alternative 5" exons and hence differ only at the N-terminus, which forms part of the first extracellular domain.

CRH-R2 mRNA is mainly expressed in peripheral tissue, particularly in cardiac myocytes, lung, skeletal muscles, ovary and gastrointestinal tract.

In the brain, the highest densities are in the parvovetricular nucleus of the hypothalamus, the amygdala and the lateral septum.

More recently, in the diploid catfish species, a third CRH receptor (CRH-R3), has been identified. This novel CRH receptor is structurally closer to cat-fish CRH-R1 than CRh-R2 and binds with a 5-fold higher affinity than urotensin I abd sauvagne. CRH-R3 in the catfish is expressed in the pituitary gland, urophysis and brain.

This multiplicity is receptor subtypes and ligands provides for diversity of receptor expression and signalling.

CRH receptor sensitivity

Mammalian CRH-R1 receptors have an equal, yet high affinity for CRH, urocortin, sauvagne and urotensin I, while not showing any affinity for urocortin II or III.

In contrast, CRH-R2 receptors show a clear preference in their affinity for urocortin-like ligands.

Urocortins I, II and III, all show high-affinity binding to CRH-R2, while mammalian CRH binds weakly.

CRH receptors are highly promiscuous. Not only do they bind a number of different ligands, but they can also activate different G-alpha subunits. Due to the complex nature of mammalian cells, the precise details of the coupling of the CRH receptors to their cognate G-protein are unknown.

LAB YEAST-CRH EXPERIENCE:

To investigate such coupling, we have utilized a YEAST reporter strain in which the pheromone-response pathways were adapted to allow ligand-dependent signalling of heterologously G-proteins or or YEAST-mammalian chimaeric G-alpha proteins.

We expressed one representative of each family of CRH receptors (CRH-R1 alpha and CRH-R2 beta) within SCHIZOSACCHAROMYCES pombe cells.

(Schizosaccharomyces pombe, also called "fission yeast", is a species of yeast. It is used as a model organism in molecular and cell biology.) - wikipedia)
http://en.wikipedia.org/wiki/Schizosaccharomyces_pombe

Due to modifications of the cell, the CRH receptor subtypes were the only GPCRs present within the cell.

When the cells were challenged with exogenous CRH, we observed functional coupling and signalling of the CRH-R1 alpha receptor via Gas and Gai.
In contrast, urocortin I activated Gas and Gaq.

Urocortins II and III did not activate any G-proteins. Using cells transfected with CRH-R2b, we confirmed that urocortins II and III signal via this receptor subtype.

These results are as expected, since CRH has a high affinity for CRH-R1 receptors,
but only a low affinity for type 2 receptors.

Contained within this study, we investigated a number of different ligands, and made changes to
components within the Sz. pombe cells to allow a more accurate evaluation of CRH signalling.

From our results it is clear that CRH-receptor±G-protein coupling}signalling is far from simple,
and may occur in a ligand-dependent manner.

The understanding of the precise nature of CRH signalling for both receptor families and each receptor subtype is of paramount importance in understanding stress responses.

Intracellular signalling molecules

In many tissues (e.g. brain, heart, myometrium), stimulation of either type of CRH receptor by CRH or CRH-related peptides leads to the activation of adenylate cyclase and increased cAMP levels.

However, in certain tissues (i.e. testes, placenta), CRH is unable to activate the adenylate cyclase pathway, whereas it can stimulate alternative signalling cascades, such as stimulation of phosphoinositol hydrolysis, but with reduced efficacy.

As mentioned above, several studies in native tissues and artificial expression systems have demonstrated multiple G-protein activation, a finding that predicts activation of several different second messenger signals and suggests that CRH and CRH-related peptides can generate various responses in different target tissues.

Indeed, it has been shown thus far that the CRH receptors can modulate various intacellular signals, such as protein kinase.

Protein kinase, nitric oxide synthase, guanylate cyclase, prostaglandins, steroidogenic enzymes, FasL production and apoptosis.

The CRH-receptor±MAPK interaction appears to be of particular interest, since in some
cellular systems (myometrial or HEK cells overexpressing CRH receptors), urocortin or
sauvagine, but not CRH, can activate the p42}p44 MAPK system [47,48].

This effect appears to be mediated primarily, but not exclusively, via activation of the Gq±InsP$±PKC pathway.

Studies on G-protein activation and second messenger
production demonstrated that urocortin was significantly more potent than CRH in activating the Gq±InsP$±PKC pathway.

This shows the central role of the agonist±CRH-receptor±G-protein complex in determining activation of signalling cascades.

In contrast, in neuronal and hippocampal cells, both CRH and urocortin can activate the MAPK cascade, a signalling pathway that mediates the neuroprotective effects of these peptides
[49,50]; this appears to occur via activation of the Gs}adenylate cyclase system.

Without any doubt, many more studies are required to elucidate the signalling pathways that are influenced by the family of CRH peptides in different tissues.

SEE THE BOOK AT:

http://www.biochemsoctrans.org/bst/030/0428/0300428.pdf

Vol. 12, Issue 11, 3631-3643, November 2001

Signaling through Adenylyl Cyclase Is Essential for Hyphal Growth and Virulence in the Pathogenic Fungus Candida albicans

Cintia R. C. Rocha,* Klaus Schröppel, Doreen Harcus,* Anne Marcil,* Daniel Dignard,* Brad N. Taylor, David Y. Thomas,*§ Malcolm Whiteway,*§ and Ekkehard Leberer*¶

*Eukaryotic Genetics Group, Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec H4P 2R2, Canada; the Institute of Clinical Microbiology, Immunology, and Hygiene, University of Erlangen, D-91054 Erlangen, Germany; and the Departments of Anatomy and Cell Biology, §Biology, and Experimental Medicine, McGill University, Montreal, Canada

The human fungal pathogen Candida albicans switches from a budding yeast form to a polarized hyphal form in response to various external signals.

This morphogenetic switching has been implicated in the development of pathogenicity.

We have cloned the CaCDC35 gene encoding C. albicans adenylyl cyclase by functional complementation of the conditional growth defect of Saccharomyces cerevisiae cells with mutations in Ras1p and Ras2p.

It has previously been shown that these Ras homologues regulate adenylyl cyclase in yeast.

The C. albicans adenylyl cyclase is highly homologous to other fungal adenylyl cyclases but has less sequence similarity with the mammalian enzymes.

C. albicans cells deleted for both alleles of CaCDC35 had no detectable cAMP levels, suggesting that this gene encodes the only adenylyl cyclase in C. albicans.

The homozygous mutant cells were viable but grew more slowly than wild-type cells and were unable to switch from the yeast to the hyphal form under all environmental conditions that we analyzed in vitro. Moreover, this morphogenetic switch was completely blocked in mutant cells undergoing phagocytosis by macrophages.

However, morphogenetic switching was restored by exogenous cAMP.

On the basis of epistasis experiments, we propose that CaCdc35p acts downstream of the Ras homologue CaRas1p.

These epistasis experiments also suggest that the putative transcription factor Efg1p and components of the hyphal-inducing MAP kinase pathway depend on the function of CaCdc35p in their ability to induce morphogenetic switching.

Homozygous cacdc35 cells were unable to establish vaginal infection in a mucosal membrane mouse model and were avirulent in a mouse model for systemic infections.

These findings suggest that fungal adenylyl cyclases and other regulators of the cAMP signaling pathway may be useful targets for antifungal drugs.

http://www.molbiolcell.org/cgi/content/abstract/12/11/3631

Cyclic adenosine monophosphate (cAMP)
From Wikipedia, the free encyclopedia

Cyclic adenosine monophosphate (cAMP, cyclic AMP or 3'-5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is derived from adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.

cAMP is synthesised from ATP by adenylyl cyclase located at the cell membranes.
cAMP and its associated kinases function in several biochemical processes, including the regulation of glycogen, sugar, and lipid metabolism.

Some research has suggested that a deregulation of cAMP pathways and an aberrant activation of cAMP-controlled genes is linked to the growth of some cancers.

http://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate

Copyright © 1997 Published by Elsevier Science B.V.

Glycosyl-phosphatidylinositol anchored membrane enzymes (GPI anchors)

Nigel M. Hooper,
School of Biochemistry and Molecular Biology, The University of Leeds, Leeds LS2 9JT, UK
Received 20 October 1996; accepted 23 July 1997. ; Available online 11 March 1999.

Abstract

Several mammalian enzymes are anchored to the outer surface of the plasma membrane by a covalently attached glycosyl-phosphatidylinositol (GPI) structure.

These include acetylcholinesterase, alkaline phosphatase, membrane dipeptidase and 5′-nucleotidase.

All GPI anchors determined to date have the conserved core structure ethanolamine-PO4-6Manα1-2Manα1-6Manα1-4GlcNH2α1-6myo-inositol-1-PO−4 lipid.

In most mammalian GPI anchors the lipid is 1-alkyl-2-acyl-glycerol, although in porcine membrane dipeptidase it is diacylglycerol.

Attached to the conserved core are various side chain residues that appear to be either protein- or tissue-specific.

In addition to membrane attachment, a GPI anchor may confer additional properties on the protein, such as the susceptibility to cleavage by phospholipases and the potential to cluster in detergent-insoluble domains.

GPI anchors can also act as intracellular targeting signals, in transmembrane signalling, in the clathrin-independent endocytic process of potocytosis and as hormone mediators.

Thus, a GPI anchor can confer additional properties on enzymes that may be important in their physiological and pathophysiological functioning.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T57-3W0K17R-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1062001067&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=05e1d002f735043de9be6fd944c73467

Resistance to candidiasis and macrophage activity in chitin-treated mice

Aitor Rementeríaa, Fernando Abaituaa, Roberto García-Tobalinaa, Fernando Hernandoa, José Pontóna, María Jesús Sevillaa
a Departamento de Inmunología, Microbiología y Parasitología, Universidad del País Vasco, Apdo. 644, Bilbao, E-48080, Spain

The effect of chitin, a polysaccharide of the cell wall of Candida albicans, on both the survival of C. albicans infected mice and the activity of the murine peritoneal macrophages has been studied. Pretreatment of mice with 30 mg kg−1C. albicans chitin enhanced the survival of the infected animals. The protective effect was concomitant with an enhancement of both phagocytic and candidacidal activities of the peritoneal macrophages. Chitin by itself did not induce the nitric oxide (NO) synthase in the macrophages, which remained at a level similar to that shown by the macrophages from untreated animals. The administration of 10 mg kg−1C. albicans chitin diminished the long term survival of the infected animals. This effect was coincident with a lower candidacidal activity and NO production by the macrophages of the chitin treated and infected animals, compared to the untreated infected animals.

Received 15 May 1997, Revised 18 July 1997, Accepted 23 July 1997

http://www3.interscience.wiley.com/journal/119157751/abstract?CRETRY=1&SRETRY=0
Crh1p and Crh2p are required for the cross-linking of chitin to β(1-6)glucan in the Saccharomyces cerevisiae cell wall

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)(1) National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Biochemistry and Genetics, Bethesda, MD 20892, ETATS-UNIS(2) Departamento de Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, ESPAGNE

Résumé / Abstract

In budding yeast, chitin is found in three locations:
-at the primary septum, largely in free form,
-at the mother-bud neck, partially linked to β(1-3)glucan,
-and in the lateral wall, attached in part to β(1-6)glucan.

By using a recently developed strategy for the study of cell wall cross-links, we have found that chitin linked to β(1-6)glucan is diminished in mutants of the CRH1 or the CRH2/UTR2 gene and completely absent in a double mutant.

This indicates that Crh1p and Crh2p, homologues of glycosyltransferases, ferry chitin chains from chitin synthase III to β(1-6)glucan.

Deletion of CRH1 and/or CRH2 aggravated the defects of fks1Δ and gas1Δ mutants, which are impaired in cell wall synthesis.

A temperature shift from 30°C to 38°C increased the proportion of chitin attached to β(1-6)glucan.

The expression of CRH1, but not that of CRH2, was also higher at 38°C in a manner dependent on the cell integrity pathway.

Furthermore, the localization of both Crh1p and Crh2p at the cell cortex, the area where the chitin-β(1-6)glucan complex is found, was greatly enhanced at 38°C.

Crh1p and Crh2p are the first proteins directly implicated in the formation of cross-links between cell wall components in fungi.

http://cat.inist.fr/?aModele=afficheN&cpsidt=18487525

Increased susceptibility to disseminated Candidiasis in interleukin-6 deficient mice

2009-10-16T12:54:00.000-07:00

HOME PAGE

Increased susceptibility to disseminated Candidiasis in interleukin-6 deficient mice.

van Enckevoort F, Netea MG, Hermus A, Sweep CG, van der Meer JW, Kullberg BJ; Interscience Conference on Antimicrobial Agents and Chemotherapy. Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1998 Sep 24-27; 38: 296 (abstract no. G-43).
Univ. Hosp. Nijmegen, The Netherlands.
Interleukin-6 (IL-6) is a multifunctional cytokine that regulates multiple aspects of the innate immune response. It has been recently shown that endogenous IL-6 is crucial for an efficient defense against severe infections with Gram- negative and Gram-positive bacteria. The aim of the present study was to investigate the role of endogenous IL-6 in the defense against infection with the yeast Candida albicans. When infected with 3x10(5) CFU/mouse, IL-6 deficient mice (IL-6-/-) had a significantly decreased survival when compared with IL-6+/+ controls (30 vs. 70%, p<0.05). href="http://gateway.nlm.nih.gov/MeetingAbstracts/102188063.html">http://gateway.nlm.nih.gov/MeetingAbstracts/102188063.html

Peripheral corticotropin-releasing factor mediates the elevation of plasma IL-6 by immobilization stress in rats

Auteur(s) / Author(s)ANDO T. (1) ; RIVIER J. (2) ; YANAIHARA H. (1) ; ARIMURA A. (1) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)(1) United States-Japan Biomedical Research Laboratories, Tulane University Hebert Center, Belle Chasse, Louisiana 70037-3001, ETATS-UNIS(2) Peptide Biology Laboratory, Salk Institute, La Jolla, California 92037, ETATS-UNIS

Résumé / AbstractWe previously reported the elevation of plasma interleukin (IL)-6 activity in response to immobilization stress in rats. To investigate the role of peripheral corticotropin-releasing factor (CRF) in this response, we examined the effects of CRF antagonists on immobilization-induced IL-6 response. Intravenous pretreatment with either [D-Phe12,Nle21,38,CαMeLeu37]-anti-human rat (h/r) CRF12-41 (1.5 mg/kg) or cyclo(30-33)[D-Phe12, Nle21,38,Glu30,Lys33]-h/rCRF12-41 (Astressin, 0.5 mg/kg) attenuated the IL-6 response to immobilization, which confirmed our previous finding that systemic administration of an antiserum against CRF blocked this response. In addition, an intraperitoneal injection of h/rCRF (100 μg/kg) or rat urocortin (10 and 100 μg/kg) increased the plasma IL-6 activity, mimicking the response to immobilization. An intravenous injection of h/rCRF (100 μg/kg) also elevated plasma IL-6 in adrenalectomized rats. These findings suggest that peripheral CRF mediates the plasma IL-6 elevation in response to immobilization.

http://cat.inist.fr/?aModele=afficheN&cpsidt=1770729

Protective effect of alprazolam against sleep deprivation-induced behavior alterations and oxidative damage in mice

2009-10-16T11:42:00.000-07:00

Protective effect of alprazolam against sleep deprivation-induced behavior alterations and oxidative damage in mice.

Singh A, Kumar A.
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.

Sleep deprivation is considered as a risk factor for various diseases.

Sleep deprivation leads to behavioral, hormonal, neurochemical and biochemical alterations in the animals.

The present study was designed to explore the possible involvement of GABAergic mechanism in protective effect of alprazolam against 72h sleep deprivation-induced behavior alterations and oxidative damage in mice.

In the present study, sleep deprivation caused
anxiety-like behavior,
weight loss,
impaired ambulatory movements and
oxidative damage
as indicated by
increase in lipid peroxidation,
nitrite level and
depletion of reduced glutathione and catalase activity

in sleep-deprived mice brain.

Treatment with alprazolam (0.25 and 0.5 mg/kg, ip) significantly improved behavioral alterations.

Biochemically, alprazolam treatment significantly restored depleted reduced glutathione, catalase activity,
reversed raised lipid peroxidation and nitrite level.

Combination of flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) with lower dose of alprazolam (0.25mg/kg) significantly antagonized protective effect of alprazolam.

However, combination of muscimol (0.05 mg/kg) with alprazolam (0.25 mg/kg, ip) potentiated protective effect of alprazolam.

On the basis of these results, it might be suggested that alprazolam might produce protective effect by involving GABAergic system against sleep deprivation-induced behavior alterations and related oxidative damage.

PMID: 18280601 [PubMed - indexed for MEDLINE]

Glutathione
From Wikipedia, the free encyclopedia

Glutathione (GSH) is a tripeptide. It contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side chain. Glutathione, an antioxidant, helps protect cells from reactive oxygen species such as free radicals and peroxides.[2] Glutathione is also nucleophile at sulfur and attacks poisonous conjugate acceptors.
Thiol groups are kept in a reduced state at a concentration of approximately ~5 mM in animal cells. In effect, glutathione reduces any disulfide bond formed within cytoplasmic proteins to cysteines by acting as an electron donor. In the process, glutathione is converted to its oxidized form glutathione disulfide (GSSG). Glutathione is found almost exclusively in its reduced form, since the enzyme that reverts it from its oxidized form, glutathione reductase, is constitutively active and inducible upon oxidative stress. In fact, the ratio of reduced glutathione to oxidized glutathione within cells is often used scientifically as a measure of cellular toxicity.[3]

Function in animals

GSH is known as a substrate in both conjugation reactions and reduction reactions, catalyzed by glutathione S-transferase enzymes in cytosol, microsomes, and mitochondria. However, it is also capable of participating in non-enzymatic conjugation with some chemicals, as in the case of N-acetyl-p-benzoquinone imine (NAPQI), the reactive cytochrome P450-reactive metabolite formed by paracetamol (or acetaminophen as it is known in the US), that becomes toxic when GSH is depleted by an overdose of acetaminophen.

Glutathione conjugates to NAPQI and helps to detoxify it, in this capacity protects cellular protein thiol groups, which would otherwise become covalently modified; when all GSH has been spent, NAPQI begins to react with the cellular proteins, killing the cells in the process.

The preferred treatment for an overdose of this painkiller is the administration (usually in atomized form) of N-acetyl-L-cysteine, which is processed by cells to L-cysteine and used in the de novo synthesis of GSH.

Glutathione (GSH) participates in leukotriene synthesis and is a cofactor for the enzyme glutathione peroxidase.

It is also important as a hydrophilic molecule that is added to lipophilic toxins and waste in the liver during biotransformation before they can become part of the bile. Glutathione is also needed for the detoxification of methylglyoxal, a toxin produced as a by-product of metabolism.

This detoxification reaction is carried out by the glyoxalase system. Glyoxalase I (EC 4.4.1.5) catalyzes the conversion of methylglyoxal and reduced glutathione to S-D-lactoyl-glutathione. Glyoxalase II (EC 3.1.2.6) catalyzes the hydrolysis of S-D-lactoyl-glutathione to glutathione and D-lactic acid.

Glutathione has recently been used as an inhibitor of melanin in the cosmetics industry. In countries like the Philippines, this product is sold as a whitening soap. Glutathione competitively inhibits melanin synthesis in the reaction of tyrosinase and L-DOPA by interrupting L-DOPA's ability to bind to tyrosinase during melanin synthesis.

The inhibition of melanin synthesis was reversed by increasing the concentration of L-DOPA, but not by increasing tyrosinase. Although the synthesized melanin was aggregated within 1 h, the aggregation was inhibited by the addition of glutathione.

These results indicate that glutathione inhibits the synthesis and agglutination of melanin by interrupting the function of L-DOPA. "[17]

silymarin or milk thistle has also demonstrated an ability to replenish glutathione levels!!!

Glutathione is a tightly regulated intracellular constituent and is limited in its production by negative feedback inhibition of its own synthesis through the enzyme gamma-glutamylcysteine synthetase, thus greatly minimizing any possibility of overdosage.

Glutathione augmentation is a strategy developed to address states of glutathione deficiency, high oxidative stress, immune deficiency, and xenobiotic overload in which glutathione plays a part in the detoxification of the xenobiotic in question.

Glutathione deficiency states include, but are not limited to: HIV/AIDS, chemical and infectious hepatitis, prostate and other cancers, cataracts, Alzheimer's, Parkinsons, chronic obstructive pulmonary disease, asthma, radiation poisoning, malnutritive states, arduous physical stress, aging, and has been associated with sub-optimal immune response. Many clinical pathologies are associated with oxidative stress and are elaborated upon in numerous medical references.[44]

Low glutathione is also strongly implicated in wasting and negative nitrogen balance, [45] notably as seen in cancer, AIDS, sepsis, trauma, burns and even athletic overtraining. Glutathione supplementation can oppose this process and in AIDS, for example, result in improved survival rates.[46]

http://en.wikipedia.org/wiki/Glutathione

the 'organ Km' for glutathione in the liver is approximately 0.5 mumol/g of liver, so that the hepatic glutathione conjugation rate is decreased only at severe glutathione depletion.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1132802/

Catalase
From Wikipedia, the free encyclopedia

Catalase is a common enzyme found in nearly all living organisms which are exposed to oxygen, where it functions to catalyze the decomposition of hydrogen peroxide to water and oxygen.[1]

Grey hair
According to recent scientific studies, low levels of catalase may play a role in the greying process of human hair. Hydrogen peroxide is naturally produced by the body and catalase breaks it down. If there is a dip in catalase levels, hydrogen peroxide cannot be broken down. This causes the hydrogen peroxide to bleach the hair from the inside out. Scientists believe this finding may someday lead to "anti" greying treatments for aging hair.[30][31][32]

http://en.wikipedia.org/wiki/Catalase

STRESS-INDUCED SLEEP DEPRIVATION MODIFIES CORTICOTROPIN RELEASING FACTOR (CRF) LEVELS

2009-10-16T11:38:00.000-07:00

Copyright © 1997 The Italian Pharmacological Society. Published by Elsevier Science Ltd.
Regular Article

STRESS-INDUCED SLEEP DEPRIVATION MODIFIES CORTICOTROPIN RELEASING FACTOR (CRF) LEVELS AND CRF BINDING IN RAT BRAIN AND PITUITARY *1

PAOLA FADDAa, f1 and WALTER FRATTAb
a ‘B.B. Brodie’ Department of Neuroscience, University of Cagliari, Cagliari, Italy
b Center for Neuropharmacology, National Research Council University of Cagliari, Cagliari, Italy
Accepted 2 April 1997. ;
Available online 15 April 2002.

Abstract

Electroencephalographic (EEG) studies have shown that corticotropin-releasing factor (CRF) administration induces EEG activation, decreases sleep time both in rats and humans and modifies the sleep pattern in sleep deprived rats.

In the present study we have investigated whether CRF neuronal activity could be altered in a situation of disrupted sleep-wake cycle.

Sleep deprivation (SD) was induced by keeping the rat for 72 h on a small platform (7 cm) surrounded by water.

Immediately after the SD period rats were killed and CRF levels and CRF receptor binding were evaluated in different brain areas.

A marked increase in CRF levels was present in the striatum (+224%), limbic areas (+144%) and pituitary (+42%) whereas the hypothalamic CRF content was reduced (−57%).

A significant decrease in CRF binding was found in the striatum (−33%) and pituitary (−38%) of sleep deprived rats.

These results indicate that CRF neuronal activity is stimulated by SD, suggesting that CRF might play an important role in the physiological regulation of the sleep-wake cycle and that an altered CRF neuronal activity might be involved in behavioral modifications related to sleep disturbances.

Author Keywords: Sleep deprivation; corticotropin-releasing factor; limbic system; striatum; rat

*1 De Souza, EBNemeroff, CB
f1 Correspondence to: Paola Fadda, ‘B.B. Brodie’ Department of Neuroscience, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WP9-45KKVFG-2V&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1051469287&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=643478cc8d82373b16a116de18bfa062

Immobilisation stress induces a paradoxical sleep rebound in rat

2009-10-16T11:25:00.000-07:00

Immobilisation stress induces a paradoxical sleep rebound in rat

Rampin C, Cespuglio R, Chastrette N, Jouvet M.

Département de Médecine Expérimentale, INSERM U 52, CNRS URA 1195, Université Claude Bernard, Lyons, France.

An immobilisation stress (IS) of 2 h applied to rats at the beginning of the dark period (12 h), i.e. when the animals are more active, induces during the 10 consecutive h a significant rebound (+92%) of paradoxical sleep (PS) while slow-wave sleep state (SWS) is poorly affected. Two h of sleep deprivation, also applied at the beginning of the dark period and realized either by the platform technique or by maintaining the animals awake with gentle handling, do not affect significantly subsequent SWS and PS. Finally, when repetitive IS are inflicted to the animals (one IS of 2 h every 3 days) an attenuation of the PS rebound is observed.

These data suggest that a qualitative aspect of the waking state as in an intense stressful situation might be the source of a hormonal process inducing a PS (paradoxical sleep) excess.

PMID: 1922920 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/1922920

Involvement of stress in the sleep rebound mechanism induced by sleep deprivation in the rat: use of alpha-helical CRH(9-41)

González, M M del C.; Valatx, J-L

Abstract

A previous study demonstrated the efficacy of the corticotropin-releasing hormone (CRH) receptor antagonist, [alpha] -helical CRH (9-41), in blocking the paradoxical sleep increase induced by stress.

In the present study, this peptide was used to evaluate the involvement of the stress component of the sleep deprivation, in the paradoxical sleep rebound.

Rats were subjected for 10 h to the classical water-tank sleep-deprivation technique and were given, every 2 h throughout the sleep deprivation period, intracerebroventricular injections of either 100 [micro]g/5 [micro]I of a-helical CRH (9-41) or vehicle alone.

Continuous recordings showed that antagonist treatment decreased the PS rebound, but not the SWS rebound, following sleep deprivation.

These findings suggest that, in the water-tank sleep deprivation method, stress, acting via CRH activation, is the main factor inducing the paradoxical sleep rebound.

(C) 1998 Lippincott Williams & Wilkins, Inc.

http://journals.lww.com/behaviouralpharm/Abstract/1998/12000/Involvement_of_stress_in_the_sleep_rebound.1.aspx

Sleep deprivation effects on the activity of the hypothalamic–pituitary–adrenal and growth axes: potential clinical implications

2009-10-16T11:18:00.000-07:00

Sleep deprivation effects on the activity of the hypothalamic–pituitary–adrenal and growth axes: potential clinical implications

Alexandros N. Vgontzas , George Mastorakos , Edward O. Bixler , Anthony Kales , Philip W. Gold & George P. Chrousos

1 Sleep Research and Treatment Center, Department of Psychiatry, Pennsylvania State University, Hershey, USA, 2 Endocrine Unit, Evgenidion Hospital, Athens University, Athens, Greece, 3 Clinical Neuroendocrinology Branch, National Institute of Mental Health, Bethesda, USA, 4 Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA

Correspondence to: Dr Alexandros N. Vgontzas Sleep Research and Treatment Center, Department of Psychiatry Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Fax: +1 (717) 531 6491.
Copyright 1999 Blackwell Science Ltd

ABSTRACT

OBJECTIVES

Although several studies have shown that sleep deprivation is associated with increased slow wave sleep during the recovery night, the effects of sleep deprivation on cortisol and growth hormone (GH) secretion the next day and recovery night have not been assessed systematically. We hypothesized that increased slow wave sleep postsleep deprivation is associated with decreased cortisol levels and that the enhanced GH secretion is driven by the decreased activity of the HPA axis.

DESIGN AND SUBJECTS

After four consecutive nights in the Sleep Laboratory, 10 healthy young men were totally deprived of sleep during the fifth night, and then allowed to sleep again on nights six and seven. Twenty-four hour blood sampling was performed serially every 30 minutes on the fourth day, immediately following the previous night of sleep and on the sixth day, immediately after sleep deprivation.

MEASUREMENT

Eight-hour sleep laboratory recording, including electroencephologram, electro-oculogram and electromyogram. Plasma cortisol and GH levels using specific immunoassay techniques.

RESULTS

Mean plasma and time-integrated (AUC) cortisol levels were lower during the postdeprivation nighttime period than on the fourth night (P < class="invisible-anchor" name="h005">

CONCLUSION

We conclude that sleep deprivation results in a significant reduction of cortisol secretion the next day and this reduction appears to be, to a large extent, driven by the increase of slow wave sleep during the recovery night.

We propose that reduction of CRH and cortisol secretion may be the mechanism through which sleep deprivation relieves depression temporarily.

Furthermore, deep sleep has an inhibitory effect on the HPA axis while it enhances the activity of the GH axis. In contrast, sleep disturbance has a stimulatory effect on the HPA axis and a suppressive effect on the GH axis.

These results are consistent with the observed hypocortisolism in idiopathic hypersomnia and HPA axis relative activation in chronic insomnia.

Finally, our findings support previous hypotheses about the restitution and immunoenhancement role of slow wave (deep) sleep.

http://www3.interscience.wiley.com/journal/118881160/abstract?CRETRY=1&SRETRY=0

Tetrahydroprogesterone counteracts corticotropin-releasing hormone-induced anxiety and alters the release of corticotropin-releasing hormone

2009-10-10T14:38:00.000-07:00

The neurosteroid tetrahydroprogesterone counteracts corticotropin-releasing hormone-induced anxiety and alters the release and gene expression of corticotropin-releasing hormone in the rat hypothalamus.

Patchev VK, Shoaib M, Holsboer F, Almeida OF.Department of Neuroendocrinology, Max Planck Institute for Psychiatry, Munich, Germany.

The ring-A-reduced progesterone derivative 5 alpha-pregnan-3 alpha-ol-20-one (tetrahydroprogesterone) is synthesized under normal physiological conditions in the brain and is a potent modulator of the GABA receptor.

This neurosteroid has significant sedative and anxiolytic properties.

Corticotropin-releasing hormone plays a major role in stress-induced activation of the hypothalamo-pituitary-adrenal axis, and sustained hyperactivity of hypothalamic corticotropin-releasing hormone-producing neurons may be causally related to both, increased pituitary-adrenal secretion and behavioural symptoms observed in anxiety and affective disorders. We investigated the effect of tetrahydroprogesterone on corticotropin-releasing hormone-induced anxiety, the basal and methoxamine-stimulated release of corticotropin-releasing hormone from hypothalamic organ explants in vitro, and adrenalectomy-induced up-regulation of the gene expression of corticotropin-releasing hormone in the hypothalamic paraventricular nucleus in rats. At doses of 5 and 10 micrograms i.c.v., tetrahydroprogesterone counteracted the anxiogenic action of 0.5 microgram of corticotropin-releasing hormone.

Tetrahydroprogesterone did not alter the basal release of corticotropin-releasing hormone in vitro, but suppressed the stimulatory effect of the alpha 1-adrenergic agonist methoxamine on this parameter. Measurements of the steady-state levels of mRNA coding for corticotropin-releasing hormone by quantitative in situ-hybridization histochemistry revealed that tetrahydroprogesterone was equipotent with corticosterone in preventing adrenalectomy-induced up-regulation of peptide gene expression.

Systemic administration of tetrahydroprogesterone also restrained adrenalectomy-induced thymus enlargement.

These results demonstrate that tetrahydroprogesterone has anxiolytic effects that are mediated through interactions with hypothalamic corticotropin-releasing hormone in both, genomic and non-genomic fashions.

http/www.ncbi.nlm.nih.gov/pubmed/7816204

Allopregnanolone (tetrahydroprogesterone)

From Wikipedia, the free encyclopedia

Allopregnanolone, also known as 3α,5α-tetrahydroprogesterone or THP, is an important neurosteroid in the human brain.

It is a metabolite of progesterone and a barbiturate-like modulator of central gamma-aminobutyric acid (GABA) receptors that modify a range of behaviors, including the stress response.

The 5β epimer of this compound is known as pregnanolone, and has very similar properties to allopregnanolone.

Both compounds are found endogenously and have similar hypnotic and anxiolytic effects.

http/en.wikipedia.org/wiki/Allopregnanolone

Tetrahydroprogesterone Attenuates the Endocrine Response to Stress

2009-10-10T14:37:00.000-07:00

Neuropsychopharmacology (1996) 15 533-540.

The Neurosteroid Tetrahydroprogesterone Attenuates the Endocrine Response to Stress and Exerts Glucocorticoid-like Effects on Vasopressin Gene Transcription in the Rat Hypothalamus

V K Patchev MD, Ph.D, A H S Hassan B.V.Sc, Ph.D, F Holsboer MD, Ph.D and O F X Almeida Ph.D From the Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Clinical Institute, Munich, GermanyCorrespondence: V K Patchev, Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Clinical Institute, Kraepelinstr. 2, 80804 Munich, Germany. E-mail: patchev@mpipsykl.mpg.de

ABSTRACT

The neurosteroid tetrahydroprogesterone (5-pregnan-3-ol-20-one, allopregnanolone, THP), has been previously shown to counteract the anxiogenic effects of corticotropin-releasing hormone (CRH) and to interfere with noradrenergic and corticosteroid-mediated regulation of CRH release and gene transcription.

Those observations indicated that, besides its sedative and analgesic activity, THP may also affect the neuroendocrine response to stress in a mode resembling that of corticosteroids. To examine this possibility, we compared the ability of THP, its precursor progesterone (P4), and the glucocorticoids dexamethasone (DEX) and corticosterone (CORT) to influence the pituitary-adrenal response to acute emotional stress and the adrenalectomy-induced increase in the gene transcription of the stress-related peptide arginine vasopressin (AVP) and of corticosteroid receptors (MR and GR) in the brain. Pretreatment of rats with a single dose of THP or P4 (50 g/kg) significantly attenuated the elevation of plasma adrenocorticotropin (ACTH) and serum corticosterone after emotional stress; both steroids were, however, less potent than a similar dose of DEX. Administration of 1 mg of THP, CORT, or P4 to adrenalectomized (ADX) rats attenuated the increase in AVP mRNA levels in the ventromedial subdivision of the hypothalamic paraventricular nucleus (PVN), as compared with vehicle-treated ADX rats. However, whereas CORT and P4 influenced the ADX-induced increase in the transcription of both types of corticosteroid receptors in the hippocampus, these were unaffected by THP. In contrast to the glucocorticoids, THP and P4 failed to decrease plasma ACTH levels in rats deprived of endogenous steroids.

These results demonstrate that the neurosteroid THP and its precursor P4 resemble glucocorticoids in their suppression of the pituitary-adrenal response to emotional stress;

however, THP influences the transcription of glucocorticoid-responsive genes in brain structures involved in the regulation of the hypothalamo-pituitary-adrenal system in a fashion that is quite distinct from that obtained with glucocorticoids.

Ó American College of NeuropsychopharmacologyKeywords: Neurosteriods; Progesterone; Glucocorticoids; Vasopressin; Corticosteroid receptors; Stress

http://www.nature.com/npp/journal/v15/n6/abs/1380502a.html

Corticotropin-releasing factor (CRF) and endocrine responses to stress: CRF receptors, binding protein, and related peptides

2009-10-10T14:35:00.000-07:00

Corticotropin-releasing factor (CRF) and endocrine responses to stress: CRF receptors, binding protein, and related peptides.

Turnbull AV, Rivier C.Clayton Foundation Laboratory of Peptide Biology, Salk Institute, La Jolla, California 92037, USA.

Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide, which is recognized as a critical mediator of complimentary, stress-related endocrine, autonomic, and behavioral responses in mammalian species.

CRF belongs to a family of structurally related peptides including frogskin sauvagine and fish urotensin I.

The effects of CRF and related peptides are mediated by two distinct receptors, which differ in their anatomical distribution, as well as in their pharmacological characteristics.

In addition, CRF is bound with high affinity by a CRF binding protein (CRF-BP), which is a putative inhibitor of CRF action.

CRF is probably not the sole endogenous ligand for CRF receptors or the CRF-BP, since a second mammalian member of the CRF family, urocortin, has recently been identified.

This article describes recent findings with respect to CRF, its receptors, binding protein, and CRF-related peptides, which provide further insights into the role and mechanisms of CRF action in stress responses.

PMID: 9142133 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/9142133

Endogenous substance P inhibits the expression of corticotropin-releasing hormone during a chronic inflammatory stress

2009-10-10T14:32:00.000-07:00

Endogenous substance P inhibits the expression of corticotropin-releasing hormone during a chronic inflammatory stress

Copyright © 1995

Published by Elsevier Science Inc.H. S. Chowdreyxa*, P. J. Larsent, M. S. Harbuza, S. L. Lightmana and D. S. Jessopa, a Department of Medicine, University of Bristol, Bristol Royal Infirmary, Marlborough Street, Bristol BS2 8Hw, U.K.* School of Chemical and Life Sciences, University of Greenwich, London, U.K.t Department of Medical Anatomy, The Panum Institute, University of, Copenhagen, DenmarkRevised 18 September 1995.
Available online 5 April 2000.

Abstract

We have investigated the effects of a chronic inflammatory stress on substance P (SP) levels in the hypothalami of rats given adjuvant-induced arthritis (AA).

Fourteen days after injection of . substance P concentrations in the paraventricular nucleus (PVN) and median eminence/arcuate nucleus were significantly increased.

In AA rats injected intraperitoneally with the specific neurokinin-1 receptor antagonist RP67580, plasma ACTH and corticosterone concentrations were significantly elevated and corticotropin-releasing hormone (CRH) mRNA in the PVN was increased compared to the AA group which received saline alone. The increases in hypothalamic SP in AA, together with the data demonstrating that HPA axis activity is enhanced in AA following injection of a SP antagonist, are consistent with the hypothesis that SP is acting as an inhibitor of CRH expression in this model of chronic inflammatory stress.Author Keywords: substance P; CRH; ACTH; corticosterone; RP67580

http://www.sciencedirect.com/science...d93c9300c9e 5

Corticosterone and insulin interact to regulate glucose and triglyceride levels during stress in a bird

2009-10-10T13:54:00.000-07:00

Am J Physiol Regul Integr Comp Physiol 281: R994-R1003, 2001; 0363-6119/01 $5.00
Vol. 281, Issue 3, R994-R1003, September 2001

Corticosterone and insulin interact to regulate glucose and triglyceride levels during stress in a bird

Luke Remage-Healey and L. Michael Romero

Department of Biology, Tufts University, Medford, Massachusetts 02155

Captive European starlings (Sturnus vulgaris) were exposed to the stress of handling and restraint while corticosterone, glucose, and triglyceride concentrations were monitored in blood plasma.

In saline-injected controls, basal samples were taken within 3 min of disturbance with subsequent samples taken at 40, 70, and 150 min.

This was repeated at two times during the daily cycle (day and night) on two different photoperiods: short and long days.

During both photoperiods, corticosterone concentrations approximately tripled (compared with a sixfold increase in free-living starlings) and triglyceride concentrations decreased 25-45% in response to stress at both times of the day, whereas an ~25% stress-induced hyperglycemia occurred only at night.

Exogenous corticosterone (200 µg), 1.0 or 4.0 IU/kg of insulin, or a combination of corticosterone with each insulin dose was then separately administered to alter the above responses.

Insulin did not affect corticosterone or triglyceride concentrations but resulted in a dose-dependent hypoglycemia of 10-40%. Injected corticosterone resulted in supraphysiological corticosterone concentrations (three- to fivefold higher than normal), yet it did not affect the already altered plasma glucose or triglyceride concentrations.

This suggests that glucose output and triglyceride decreases were already maximal in response to handling and restraint.

However, the low glucose concentrations resulting from exogenous insulin returned to basal quicker with exogenous corticosterone but only during the day. No response to either hormone showed photoperiodic differences.

These data suggest that corticosterone's role in metabolism changes to meet varying energetic demands throughout the day.

daily rhythms; seasonal rhythms; hypoglycemia; energy metabolism

http://ajpregu.physiology.org/cgi/content/abstract/281/3/R994

CRH and ACTH directly modulate the endocrine function of trophoblasts in culture by downregulating progesterone production

2009-10-10T13:47:00.000-07:00

Regulation of progesterone production in human term trophoblasts in vitro by CRH, ACTH and cortisol (prednisolone)

Udo Jeschke1 , Ioannis Mylonas1, Dagmar-Ulrike Richter2, Ingo Höcker2, Volker Briese2, Antonis Makrigiannakis3 and Klaus Friese1(1) 1st Department of Obstetrics and Gynaecology, Ludwig-Maximilians-University of Munich, Maistrasse 11, 80337 Munich, Germany (2) Department of Obstetrics and Gynecology, University of Rostock, Rostock, Germany (3) Department of Obstetrics & Gynocology, Medical School, University of Crete, Heraklion, 71110, Greece

Received: 13 December 2004
Accepted: 11 January 2005

Published online: 16 April 2005

Abstract Background:

In most mammals, onset of labor is accompanied with progesterone withdrawal.

In humans, cortisol blockade of progesterone is a possible mechanism involved in the initiation of labor.

Therefore, aim of the study was to clarify the effect of CRH, ACTH and cortisol (prednisolone) on the release of progesterone by term trophoblast cells in vitro.

Methods: Cytotrophoblast cells were prepared from human term placentas by standard dispersion of villous tissue followed by a percoll gradient centrifugation step.

Trophoblasts were incubated with CRH, ACTH as well as with prednisolone

Results:

The release of progesterone is decreased in CRH- and ACTH-treated trophoblast cell cultures compared to untreated trophoblast cells.

Addition of prednisolone in varying concentrations leads to an increase of trophoblast progesterone production.

Conclusions:

The results suggest that CRH and ACTH directly modulate the endocrine function of trophoblasts in culture by downregulating progesterone production.

Prednisolone on the other hand showed a stimulating effect on progesterone production in term trophoblast cells in vitro.

Because blockade of progesterone is a possible mechanism involved in initiation of labor, we may speculate that CRH and ACTH are directly involved in the auto- or paracrine regulation of this procedure. Keywords CRH - ACTH - Prednisolone - Progesterone production - Trophoblast cells

http/www.springerlink.com/content/hg9txt426r9q2821/

A short luteal phase (is the period that starts at ovulation and ends on the day before the next period) that lasts less than 10 days also indicates low levels of progesterone.

http/www.buzzle.com/articles/low-progesterone.html

Effects of Psychological Stress and Alprazolam on Development of Oral Candidiasis in Rats

2009-10-10T11:00:00.000-07:00

Note: ALPRAZOLAM = XANAX

Clin Diagn Lab Immunol. 2002 July; 9(4): 852–857.
doi: 10.1128/CDLI.9.4.852-857.2002.
PMCID: PMC120028
Copyright © 2002, American Society for Microbiology

M. J. Núñez, J. Balboa, P. Riveiro, D. Liñares, P. Mañá, M. Rey-Méndez, A. Rodríguez-Cobos, J. A. Suárez-Quintanilla, L. A. García-Vallejo, and M. Freire-Garabal*

Neuroimmunology Laboratory, Department of Pharmacology, School of Medicine, University of Santiago de Compostela, 15705-Santiago de Compostela, Spain
*Corresponding author. Mailing address: Neuroimmunology Laboratory, Department of Pharmacology, School of Medicine, University of Santiago de Compostela, 15705-Santiago de Compostela, Spain. Phone: 34 600 942 256. Fax: 34 981 573 191. E-mail: fffregar@usc.es
.
Received January 29, 2001; Revised May 16, 2001; Accepted April 23, 2002.

Effects of Psychological Stress and Alprazolam on Development of Oral Candidiasis in Rats

Abstract

Psychological stress has been found to suppress cell-mediated immune responses that are important in limiting the proliferation of Candida albicans. Since anxiolytic drugs can restore cellular immunity in rodents exposed to stress conditions, we designed experiments conducted to evaluate the effects of alprazolam (1 mg/kg of body weight/day), a central benzodiazepine anxiolytic agonist, on the development of oral candidiasis in Sprague-Dawley rats exposed to a chronic auditory stressor. Animals were submitted to surgical hyposalivation in order to facilitate the establishment and persistence of C. albicans infection. Application of stress and treatment with drugs (placebo or alprazolam) were initiated 7 days before C. albicans inoculation and lasted until the end of the experiments (day 15 postinoculation). Establishment of C. albicans infection was evaluated by swabbing the inoculated oral cavity with a sterile cotton applicator on days 2 and 15 after inoculation, followed by plating on YEPD (yeast extract-peptone-dextrose) agar. Tissue injury was determined by the quantification of the number and type (normal or abnormal) of papillae on the dorsal tongue per microscopic field. A semiquantitative scale was devised to assess the degree of colonization of the epithelium by fungal hyphae. Our results show that stress exacerbates C. albicans infection of the tongues of rats. Significant increases in Candida counts, the percentage of the tongue's surface covered with clinical lesions, the percentage of abnormal papillae, and the colonization of the epithelium by fungal hyphae were found in stressed rats compared to those found in the unstressed rats. Treatment with alprazolam significantly reversed these adverse effects of stress, showing that, besides the psychopharmacological properties of this anxiolytic drug against stress, it has consequences for Candida infection.

Candida albicans is an example of an opportunistic pathogen frequently isolated from the human mouth, yet few carriers develop clinical signs of candidiasis. The most common predisposing factors to oral candidiasis are immunosuppresive therapy, immunoincompetence, and immunodeficiencies, indicating that the host immune system provides a protective mechanism against superficial invasion by Candida.
Several lines of evidence indicate that cell-mediated immunity is important in limiting the proliferation of Candida; thus, this opportunistic human pathogen preferentially causes invasive and disseminated infections in patients with defective phagocytic defenses and serious mucocutaneous infection in patients with deficiencies in T-cell function. Phagocytes appear to protect the host from fungal colonization even in the absence of adaptive immune mechanisms, while as-yet-undefined T-cell-dependent factors seem necessary for the control of C. albicans on body surfaces (31).
In our previous research, we had observed adverse effects of stress on natural and specific immune responses that may predispose the host to more severe Candida infections (22). On the other hand, treatment with benzodiazepines (BZDs), such as alprazolam, was found to attenuate some of the effects of stress on the immune systems of rodents, such as T-cell depletion, the inhibition of the blastogenic and cytotoxic activities of spleen cells (14, 15, 18), impaired delayed type hypersensitivity (38), and defects in phagocytosis (21). We have already tested this drug in laboratory animal models of infection showing a correlation between the immunoprotective effect of alprazolam and the host resistance against bacteria (16) and viruses (19, 20). Despite other known or unknown mechanisms, central pharmacological effects regulating the release of neuroendocrine hormones, such us adrenalcorticotropic hormone (ACTH), should be involved, at least in part, in the effects of alprazolam on immunocompetence. Nevertheless, there is little data on the effects of this compound on the development of fungal infection. In order to further elucidate this relationship, we studied the effects of alprazolam on the development of oral candidiasis in rats exposed to a repeated auditory stressor.

MATERIALS AND METHODS

Animals.

Two-month-old male pathogen-free rats of the Sprague-Dawley strain (Interfauna Iberica, S.A., Barcelona, Spain) weighing 180 to 200 g were used. They were housed individually in filter-top cages and screened for the presence of C. albicans by plating oral swabs on YEPD (yeast extract-peptone-dextrose) agar (Sigma Chemical Co., St. Louis, Mo.) (17, 31). The cages were kept in a temperature-controlled (22 to 24°C) and humidity-controlled animal room, with an alternating light-dark cycle (lights on at 0600 and lights off at 1800) and with food (diet A.03; Panlab, Barcelona, Spain) and sterile water ad libitum.

Procedure.

Following verification that the rats were free of C. albicans, they were randomly divided into six experimental groups of four animals each according to the treatment they were to be submitted to: group 1, control (i.e., no stress or placebo); group 2, unstressed rats injected with placebo; group 3, unstressed rats injected with alprazolam; group 4, stressed rats with no treatment; group 5, stressed rats injected with placebo; group 6, stressed rats injected with alprazolam.

Stress procedure.

The rats were subjected to a broadband noise at 100 db daily for 5 s every minute during either a 1- or 3-h period (at random) around midnight, at the height of the diurnal activity cycle (32). All stressed rats were subjected to the same stress schedule. Unstimulated rats were exposed only to the normal activity of the animal room. Stress application started 7 days before C. albicans inoculation and lasted until the end of experiments (day 15 postinoculation).

Treatment with drugs.

Alprazolam (Upjohn, Kalamazoo, Inc.) was intraperitoneally injected at a dose of 1 mg/kg of body weight in a volume of 1 ml of 1% water solution of carboxymethylcellulose per kg of body weight as a vehicle. Mice in the placebo group were intraperitoneally injected with 1 ml of diluent per kg of body weight. Drugs were administered daily at 9:30 a.m. during all periods of stress application.

Surgical hyposalivation.

As in humans, xerostomia in rats facilitates the establishment and persistence of C. albicans infection in the mouth; therefore, it constitutes a suitable animal model for the study of oral candidiasis (25). Sialoadenectomy in rats causes intense xerostomia, but the minor salivary glands, the main producers of mucin, an important barrier for mucosal permeability and a major source of immunoglobulin A, were preserved. In our experiment, xerostomia was surgically provoked in all rats 1 month before treatment with drugs and stress application were initiated. The rats were anesthetized with 44 mg of ketamine (Ketolar; Parke-Davis, Barcelona, Spain) per kg of body weight and 1 mg of diazepam (Valium; Roche, Madrid, Spain) per kg of body weight (40). The parotid salivary ducts of the animals were ligated, and the submandibular and sublingual salivary glands were surgically removed according to procedures previously described (7, 30, 31).

Source and culture of C. albicans.

The C. albicans organisms used to inoculate the rats were obtained from a patient with erythematous oral candidiasis (17). The Candida strains were grown on YEPD agar plates at room temperature (35). The isolated organisms were identified as C. albicans by a germ tube test and chlamydospore production as described by Schaar et al. (36).

Inoculation of C. albicans.

The C. albicans organisms isolated were prepared for inoculation by suspending colonies in sterile buffered saline and were washed twice by centrifugation before being resuspended in normal saline. The concentration of organisms was adjusted to 3 × 108/ml by optical density at 300 nm (3). The tongues of the animals were swabbed on 2 successive days with a cotton-tipped applicator saturated with 0.1 ml of fresh inoculum (31).

Quantification of C. albicans cells.

Establishment of C. albicans infection was evaluated by swabbing the inoculated oral cavity with a sterile cotton applicator, followed by plating on YEPD agar (25, 31). Samples were collected 2 days after inoculation and at the end of experiment. The cotton applicator was immediately immersed in 0.99 ml of sterile isotonic saline to obtain a dilution of 10−2, and it was agitated for 2 min. This dilution was considered to be 10−2. Dilutions up to 10−5 (0.1 ml) were cultured in duplicate in Sabouraud's dextrose agar at 37°C for 48 h. Candida colonies were counted in plates exhibiting between 30 and 300 colonies. Plates with less than 30 colonies in the 10−2 dilution were considered to have 101 cells (25).

Clinical lesions.

At the end of the experimental period, all animals were sacrificed by asphyxiation in a CO2 atmosphere and were then decapitated. The dorsal tongue was photographed in situ at a magnification of ×10 (3). Clinical lesions were measured with a digital imaging system (Técnicas Médicas MAB, Barcelona, Spain) and expressed as the percentage of the surface area of the tongue (percent area) that was covered with the lesions.

Tissue handling.

The tongues from the rats were hemidissected in the sagittal plane, with half of the lesion immersed in 10% buffered formalin for routine processing and the other half placed in 2.5% glutaraldehyde with 0.1 M Sorensen's phosphate buffer at 4°C (3).
Light microscopy.

Both hematoxylin and eosin and periodic acid-Schiff stains were used. C. albicans infection was assessed with a digital imaging system according to evidence of lesions and hyphal colonization on the dorsal tongue (3, 33). Tissue injury was determined by quantification of the number and type (normal, atrophic, and hypertropic) of papillae per microscopic field (magnification, ×46). A semiquantitative scale was devised to assess the degree of colonization of the epithelium by fungal hyphae. In this scale, the absence of colonization was given a score of 0, while maximal colonization, in excess of 50 hyphae, could be seen in each high-power field (magnification, ×400) was assigned a score of 4. The scores given were 1 for 1 to 5 hyphae, 2 for 6 to 15 hyphae, and 3 for 16 to 50 hyphae. The specimens were examined by one of us, who was blind as to the source. Three high-power fields per sample were examined for the light microscopy experiments.

Scanning electron microscopy preparation.

Following fixation for 24 h, the tissue was rinsed three times in buffer and postfixed in 1% phosphate-buffered osmium tetroxide (pH 7.4) for 1 h. After two buffer rinses, the specimens were dehydrated in ascending concentrations of ethanol, followed by critical point dehydration in a Denton DCP-1 critical point drying apparatus with liquid CO2. The tissue samples were affixed on aluminum stubs with silver conductive paint and were sputter-coated with gold-palladium by using a Hummer VI sputter-coating apparatus (Anatech Electronics, Garfield, N.J.). Specimens were viewed with a Zeiss 910 electron microscope (Zeiss, Oberkochen, Germany) operated at 20 kV (2).

Statistical analysis.

Statistical analysis of the quantitation of C. albicans cells in oral tissue was performed by one-way analysis of variance, followed by Bonferroni's t test. The percentage of areas of clinical lesions was analyzed by Student's t test (25). The Wilcoxon signed-rank sum test for paired comparisons and the Kruskal-Wallis test for multiple comparisons were used to determine the degree of colonization of the epithelium by fungal hyphae (33). Differences were considered significant at P < 0.05.

RESULTS

C. albicans counts at 2 and 15 days after inoculation (Table 1), as well as the percent area of clinical lesions in the dorsal tongue (Table 2), were increased in stressed rats compared with those in unstressed animals (differences, P < class="fig-table-link fig figpopup" style="TEXT-DECORATION: none" onclick="startTarget(this, 'figure', 1024, 800)" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=120028&rendertype=figure&id=f1" hoverintent_t="undefined" jquery1255197605890="2">(Fig.1)1) were observed in stressed animals (differences, P < class="fig-table-link fig figpopup" style="TEXT-DECORATION: none" onclick="startTarget(this, 'figure', 1024, 800)" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=120028&rendertype=figure&id=f2" jquery1255197605890="3">(Fig.2)2) scored higher than untreated controls (differences, P <> 0.05), with the only exception that placebo increased the degree of colonization of the epithelium in unstressed animals. In contrast, treatment with alprazolam significantly (P < 0.05) reversed the adverse effects of stress in all parameters assayed.

Clinically evident lesions and inflammatory changes of the underlying connective tissue were observed 15 days after C. albicans inoculation. The latter were found in all experimental groups, but they were more evident in stressed rats. Animals showed macroscopic focal patchy atrophy of the dorsal tongue papillae. Light microscopy showed localized dense zones of hyphal penetration of the keratin layer in the giant conical papillae and filiform papillae of the dorsal tongue. Microabscesses in the keratin and the superficial spinous layers were observed in association with hyphal invasion. The underlying connective tissue showed a mild chronic inflammatory cell infiltrate. Those papillae that supported the Candida growth appeared shorter and blunter than the surrounding uninfected papillae.

Scanning electron microscopy of the dorsal tongues showed a higher loss of papillae in the giant conical and filiform areas of the specimens together with an increase in the size of the flat central portion of the lesion in stressed rats in comparison with unstressed animals. This adverse effect of stress was also reduced by the administration of alprazolam.

DISCUSSION

Our results show that stress exacerbates C. albicans infection of the tongues of rats. Significant increases in Candida counts, the percent area of clinical lesions, the percent abnormal papillae, and the colonization of the epithelium by fungal hyphae were found in stressed rats compared with those found in unstressed animals. Treatment with alprazolam partially reversed those adverse effects of stress on the development of oral candidiasis. Alprazolam was found to reverse many of the effects of stress on C. albicans infection of the tongues of rats, including Candida counts, the percent area of clinical lesions, the percent abnormal papillae, and the colonization of the epithelium by fungal hyphae.
Clinical and experimental observations indicate that the opportunistic proclivities of this fungus vary considerably, depending on the nature of the immunological defect of the victim.

Patients with qualitative or quantitative defects of phagocytes are mainly prone to the invasive form of this mycosis (10, 11, 37).

In contrast, defective T-cell-mediated immunity has been specifically associated with thrush and other forms of candidiasis limited to mucocutaneous surfaces (11, 12, 24, 26). Krause and Schaffner (28) demonstrated that cyclosporine, a relatively selective suppressor of T-cell-mediated immunity and NK cell activity, promoted the formation of thrushlike lesions on cyst surfaces and impeded the elimination of C. albicans from such lesions, but it had no effect on systemic candidiasis induced by intravenous inoculation.
Our results are in line with the previous literature on the stress-induced modulation of the immune system. Changes in murine splenic cytotoxic activities, mediated by NK cells and cytotoxic T lymphocytes have been reported (10-12, 24, 26, 32, 37). Stress also interferes with the activity of phagocytosis and T-cell-dependent antibody responses (21, 28).
The mechanism by which stress inhibits the cellular immune response has been widely studied. A molecular basis for bidirectional communication between the immune and neuroendocrine systems has been described previously (5). Cell-to-cell communication between the immune and the neuroendocrine systems is primarily mediated by hormones and neuropeptides that reach lymphoid organs and cells through the vascular system or directly through the autonomic connections between nerve endings and lymphoid organs (1, 8). Receptor sites are present in lymphoid cells for many hormones and neurotransmitters (6, 39). A number of molecules produced by cells of the nervous system such as ACTH, PRL, opioid peptides, GH, TSH, dynorphin, dopamine, and others have been shown to have the ability to modulate immune functions.

On the other hand, humoral factors generated by the immune system, such as thymic peptides and lymphokines, modulate neuroendocrine functions. In addition, in the course of lymphocyte activation, lymphoid cells may produce hormonal substances identical to those produced by the hypophysis, such as ACTH, TSH, GH, PRL, gonadotrophin, and β-endorphin (6).
At least one of the neuroendocrine responses to stress, such as the rise in plasma corticosterone concentrations via ACTH secretion, has an easily demonstrable destructive effect on specific cells and tissues that are required for optimal immune defense (4, 34). In our previous studies, we observed a stress-induced increase in ACTH levels proportional to the decrease in T-cell populations (15). Nevertheless, in these studies, we observed that adrenalectomized mice showed a lower pattern of immunosuppression in comparison with sham-operated mice. So, this led us to believe that other neuropeptides and neurotransmitters could be involved in the immunosuppressive response to stress.

The effects of alprazolam, an anxiolytic drug with high affinity for central BZD receptors on the pathogenicity of this opportunistic fungus could be attributed, at least in part, to its well-known protective effects against the immunosuppressive response to the type of stress assayed here. The recovery of the immune state of the victim could decrease the pathogenicity of this opportunistic fungus. In this regard, in our previous studies, we demonstrated that alprazolam reversed the suppressive effects of stress on the activity of phagocytosis, T-cell populations, the blastogenic response of spleen cells, murine splenic cytotoxic activities, mediated by NK cells and CTL. Fride et al. (23) found that low doses (0.02 to 1.0 mg/kg) of alprazolam significantly increased the NK cell activity, mixed leukocyte reactivity, and mitogen-induced lymphocyte proliferation in unstressed mice.

The mechanism of action of BZDs on the immune system remains to be defined. A dual approach has been described at the present time. First, central pharmacological effects related to the central type BZD receptors that facilitate inhibitory GABA neurotransmission in the central nervous system may regulate the release of neuroendocrine hormones involved in the immune response to stress. The ability of alprazolam to decrease the stress-induced increase of ACTH levels (29) has been demonstrated to play a important role in the immunoprotective effects of this drug. Nevertheless, significant immunoenhancing effects of alprazolam were also appreciated in stressed adrenalectomized rats (15), suggesting that the modulatory effect of this BZD agonist on other neurohormones like opioid peptides, PRL, melatonin, TSH, or GH could also be involved (13).

A second aspect of the effects of BZDs is the existence of a BZD receptor with high affinity on immune cells that express the so-called peripheral specificity for BZDs (41). Nevertheless, alprazolam is described in the literature as strict central type ligand of the BZD receptor (29). Alprazolam has potent PAF antagonist properties (27) that seem to affect T-cell, B-cell, and macrophage responses under in vitro conditions (9).

One could ask whether secondary (nonimmune or biochemical) effects of the drug treatment might account for the final observations and whether or not stress might break down the state of tolerance normally associated with Candida infection (as opposed to acting solely as an immunopotentiator). Although these considerations should be taken into account, our previous data concerning the immunomodulatory effects of alprazolam under stress conditions (14, 15, 18, 21, 38) lead us to consider immune changes as the main factor involved on the effects of stress and alprazolam on the evolution of oral candidiasis in rats.

A second question concerns the biological significance of our results. Although our data at present show stress may leave the subject vulnerable to the action of C. albicans and provide evidence of a protective effect of alprazolam on the development of oral candidiasis in rats, the biological significance and health relatedness of these findings should be assessed. In this respect, differences between untreated stressed rats and placebo- or alprazolam-stressed rats are statistically significant, but in some parameters, they are not striking. Moreover, there is a relationship between differences obtained in different determinations, but there is not a mathematical correlation as expected.

The large number of interactions at molecular, cellular, and functional levels between the nervous system and the immune system characterizing the operational compositions and expressions of the neuroimmune network make complex isolation of the pathways in which stress and alprazolam may be involved in the regulation of the host defense mechanisms against infection. Nevertheless, the literature has provided evidence that stress-induced immunosuppression and alprazolam-induced immunoprotection are in a relationship with susceptibility to bacteria (16), virus (20), and, as a conclusion of the present investigation, Candida infection.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=120028

The Impact of Sleep Deprivation on Hormones and Metabolism

2009-10-10T09:12:00.000-07:00

Sleep is the main stressor on our bodies. Sleep curtailment leads to majour disorders of our endocrine system, which, in turn, weaken our bodies' ability to fight infection in particular and disease in general.

Cancer, diabetes, heart disease and many other severe maladies are caused in more cases that it is popularly believed, by stress and sleep deprivation.

I will start with an educational article which, in a few words, explains the harmful mechanism that we expose our body to when sleep deprived.

-Vera

The Impact of Sleep Deprivation on Hormones and Metabolism

Eve Van Cauter, PhD; Kristen Knutson, PhD; Rachel Leproult, PhD; Karine Spiegel, PhD

Introduction

Sleep loss can occur as a result of habitual behavior or due to the presence of a pathological condition that is associated with reduced total sleep time. This column focuses on the impact of behavioral sleep curtailment, an endemic condition in modern society, and provides evidence against the old notion that "sleep is for the mind, and not for the rest of the body."

Prevalence of Sleep Curtailment in Modern Society

Sleep curtailment is a hallmark of modern society, one that is often considered harmless and efficient. The advent of artificial light has permitted the curtailment of sleep to the minimum tolerable and an increase in the time available for work and leisure. In our 24-hour-a-day society, millions work during the night and sleep during the day, a schedule that generally results in substantial sleep loss.

Figure 1 illustrates changes in self-reported sleep duration over the past 50 years. In 1960, a survey of over 1 million people found a modal sleep duration of 8.0-8.9 hours.[1] In 2000, 2001, and 2002, polls conducted by the National Sleep Foundation indicated that the average duration of sleep for Americans had fallen to 6.9-7.0 hours.[2] Overall, sleep duration thus appears to have decreased by 1.5-2 hours during the second half of the 20th century. Today, many people are in bed only 5-6 hours per night on a regular basis.

The 2 major pathways by which sleep affects the release of hormones are the hypothalamic-pituitary axes and the autonomous nervous system.

The release of hormones by the pituitary — the "master" endocrine organ that controls the secretion of other hormones from the peripheral endocrine glands — is markedly influenced by sleep. Modulation of pituitary-dependent hormonal release is partly mediated by the modulation of the activity of hypothalamic-releasing and/or hypothalamic-inhibiting factors controlling pituitary function. During sleep, these hypothalamic factors may be activated — as in the case of growth hormone (GH)-releasing hormone — or inhibited, as is the case for corticotropin-releasing hormone.

The other pathway by which sleep affects peripheral endocrine regulation is via the modulation of autonomic nervous system activity. During deep sleep, sympathetic nervous system activity is generally decreased and parasympathetic nervous system activity is increased. Sleep loss is associated with an elevation of sympathovagal balance, with higher sympathetic but lower parasympathetic tone. Most endocrine organs are sensitive to changes in sympathovagal balance. Well-documented examples are pancreatic insulin secretion and release by the fat cells of leptin, an appetite-suppressing hormone.

A profound and generalized impact of sleep loss on the endocrine system should therefore be expected. Until recently, however, it was considered unlikely that the adverse effects of sleep deprivation on endocrine function would be long-term. The studies from which this notion was drawn examined the effects of only 1 or 2 nights of acute total sleep deprivation. In general, the data suggested that endocrine alterations that occurred during the sleepless night(s) were completely reversed during recovery sleep.

More recently, a few studies have examined the impact on hormones, metabolism, and immune function of the much more common, real-life situation — chronic partial sleep deprivation.[3-5] The earliest study measured hormonal and metabolic parameters in subjects studied after 6 days of sleep restriction (4-hour bedtime) and after full sleep recovery (6 days of 12-hour bedtime).[3] Subsequent studies examined the impact of less severe sleep restriction (6.5 hours per night) over 1 week[4] as well as the effects of short-term sleep curtailment (2 days with 4-hour vs 12-hour bedtime).[5]

Alterations of Pituitary-Dependent Hormones During Sleep Loss

The first effect of partial sleep loss on circulating levels of pituitary-dependent hormones to be documented under various study conditions is an increase in the early evening levels of the stress hormone cortisol.[3,6] Normally at that time of day, cortisol concentrations are rapidly decreasing to attain minimal levels shortly before habitual bedtime.

The rate of decrease of cortisol concentrations in the early evening was approximately 6-fold slower in subjects who had undergone 6 days of sleep restriction than in subjects who were fully rested.[3] Elevations of evening cortisol levels in chronic sleep loss are likely to promote the development of insulin resistance, a risk factor for obesity and diabetes.

The upper and middle panels of Figure 2 illustrate the impact of sleep restriction on the thyroid axis.[3] After 6 days of 4-hour sleep time, the normal nocturnal thyroid-stimulating hormone (TSH) rise was strikingly decreased, and the overall mean TSH levels were reduced by more than 30%.[3] A normal pattern of TSH release reappeared when the subjects had fully recovered. Differences in TSH profiles between the 2 bedtime conditions were probably related to changes in thyroid hormone concentrations via a negative-feedback regulation, because the free thyroxine index (FT4I) was higher in the sleep-restriction condition than in the fully rested condition (middle panels of Figure 2). Thyroid axis function was thus markedly altered by partial recurrent sleep restriction.

Figure 2.

Levels of thyroid-stimulating hormone (TSH), free thyroxine index, and leptin in sleep-deprived vs well-rested subjects. From top to bottom, 24-hour (+SEM) profiles of TSH, free thyroxine indexes, and leptin in healthy young subjects when submitted to partial sleep restriction for 6 days (4-hour sleep times; mean total sleep time during previous 2 nights, 3 hours 49 minutes; left panels) and after full sleep recovery (12-hour sleep times for 6 nights; mean total sleep time during previous 2 nights, 9 hours 3 minutes; right panels). The black bars represent the sleep periods.[3,10]

The temporal organization of GH secretion is also altered by chronic partial sleep loss.[7] The normal single GH pulse occurring shortly after sleep onset splits into 2 smaller pulses, 1 before sleep and 1 after sleep; as a result, the peripheral tissues are exposed to high GH levels for an extended period of time, which, because GH has anti-insulin-like effects, could also have an adverse impact on glucose tolerance.

Impact of Sleep Loss on Hormones Controlling Appetite

Sleeping and feeding are intricately related. Animals faced with food shortage or starvation sleep less;[8] conversely, animals subjected to total sleep deprivation for prolonged periods of time increase their food intake markedly.[9] Recent studies in humans have shown that the levels of hormones that regulate appetite are profoundly influenced by sleep duration. Sleep loss is associated with an increase in appetite that is excessive in relation to the caloric demands of extended wakefulness.

The regulation of leptin, a hormone released by the fat cells that signals satiety to the brain and thus suppresses appetite, is markedly dependent on sleep duration. After 6 days of bedtime restriction to 4 hours per night, the plasma concentration of leptin was markedly decreased, particularly during the nighttime.[10] The magnitude of this decrease was comparable to that occurring after 3 days of restricting caloric intake by approximately 900 kcal/day. But the subjects in the sleep-restriction condition received identical amounts of caloric intake and had similar levels of physical activity as when they were fully rested. Thus, leptin levels were signaling a state of famine in the midst of plenty.

In a later study, the levels of ghrelin, a peptide that is secreted by the stomach and stimulates appetite, were measured with the levels of leptin after 2 days of sleep restriction (4 hours of sleep) or sleep extension (10 hours of bedtime).[5] The subjects also assessed their levels of hunger and appetite at regular intervals. Sleep restriction was associated with reductions in leptin (the appetite suppressant) and elevations in ghrelin (the appetite stimulant) and increased hunger and appetite, especially an appetite for foods with high-carbohydrate contents. Similar findings were obtained simultaneously in a large epidemiologic study in which sleep duration and morning levels of leptin and ghrelin were measured in over 1,000 subjects.[11] The Table summarizes the remarkable concordance between the results of the 2 studies. Despite the differences in study design, both studies found a decrease in the satiety hormone leptin and an increase in appetite-stimulating ghrelin with short sleep.

Sleep loss therefore seems to alter the ability of leptin and ghrelin to accurately signal caloric need and could lead to excessive caloric intake when food is freely available. The findings also suggest that compliance with a weight-loss diet involving caloric restriction may be adversely affected by sleep restriction.

During the second half of the 20th century, the incidence of obesity has nearly doubled, and this trend is a mirror image of the decrease in self-reported sleep duration illustrated in Figure 1. The discovery of a profound alteration in the neuroendocrine control of appetite in conditions of sleep loss is consistent with the conclusions of several epidemiologic studies that revealed a negative association between self-reported sleep duration and body mass index. Taken together, the current evidence suggests a possible role for chronic sleep loss in the current epidemic of obesity.

Metabolic Implications of Recurrent Sleep Curtailment

Recent work also indicates that sleep loss may adversely affect glucose tolerance and involve an increased risk of type 2 diabetes.

In young, healthy subjects who were studied after 6 days of sleep restriction (4 hours in bed) and after full sleep recovery, the levels of blood glucose after breakfast were higher in the state of sleep debt despite normal or even slightly elevated insulin responses.[3] The difference in peak glucose levels in response to breakfast averaged ±15 mg/dL, a difference large enough to suggest a clinically significant impairment of glucose tolerance.

These findings were confirmed by the results of intravenous glucose tolerance testing.[3] Indeed, the rate of disappearance of glucose post injection — a quantitative measure of glucose tolerance — was nearly 40% slower in the sleep-debt condition than after recovery, and the acute insulin response to glucose was reduced by 30%. Glucose tolerance measured at the end of the recovery period was similar to that reported in an independent study[12] in young, healthy men, but glucose tolerance in the state of sleep debt was comparable to that reported for older adults with impaired glucose tolerance.[13]

Thus, less than 1 week of sleep restriction can result in a prediabetic state in young, healthy subjects. Of note, the adverse impact of sleep deprivation on glucose tolerance demonstrated in laboratory studies is consistent with the finding of an increased risk of symptomatic diabetes with short sleep in a cohort study of women.[14]

Multiple mechanisms are likely to mediate the adverse effects of sleep curtailment on parameters of glucose tolerance, including decreased cerebral glucose utilization, increases in sympathetic nervous system activity, and abnormalities in the pattern of release of the counterregulatory hormones cortisol and GH.

Conclusion

Clearly, sleep is not only for the brain but also for the rest of the body. Recent evidence suggests that sleep loss, a highly prevalent — and often strongly encouraged — condition in modern society could be a risk factor for major chronic diseases, including obesity and diabetes.
Supported by an independent educational grant from Pfizer/Neurocrine.

http://cme.medscape.com/viewarticle/502825

TERMINOLOGY

2009-10-10T08:01:00.000-07:00

Hypothalamus

Pituitary Gland

Adrenal Gland

Thymus Gland

Pancreas

CRH

ACTH

Cortisol

GnRH

2009-10-10T08:00:00.000-07:00

1. The Impact of Sleep Deprivation on Hormones and Metabolism

2. Effects of Psychological Stress and Alprazolam on Development of Oral Candidiasis in Rats

3. CRH and ACTH directly modulate the endocrine function of trophoblasts in culture by downregulating progesterone production

4. Corticosterone and insulin interact to regulate glucose and triglyceride levels during stress in a bird

5. Endogenous substance P inhibits the expression of corticotropin-releasing hormone during a chronic inflammatory stress

6. Corticotropin-releasing factor (CRF) and endocrine responses to stress: CRF receptors, binding protein, and related peptides

7. Tetrahydroprogesterone Attenuates the Endocrine Response to Stress

8. Tetrahydroprogesterone counteracts corticotropin-releasing hormone-induced anxiety and alters the release of corticotropin-releasing hormone

9. Sleep deprivation effects on the activity of the hypothalamic–pituitary–adrenal and growth axes: potential clinical implications

10. Immobilisation stress induces a paradoxical sleep rebound in rat

11. STRESS-INDUCED SLEEP DEPRIVATION MODIFIES CORTICOTROPIN RELEASING FACTOR (CRF) LEVELS

12. Protective effect of alprazolam against sleep deprivation-induced behavior alterations and oxidative damage in mice

13. Increased susceptibility to disseminated Candidiasis in interleukin-6 deficient mice

14. CRH and GPI-anchored Gas families are FUNGAL ANTIGENS

15. Involvement of the corticotropin-releasing hormone system in the pathogenesis of acne vulgaris

16. CRH Enhances Retention of a Spatial Memory

17. Corticotropin-Releasing Hormone (CRH) Downregulates the Function of Its Receptor (CRF1)

MY STUDY

2009-08-01T07:59:00.000-07:00

HOME PAGE

After years of alleatory reading, trying to understand the mechanism of stress, this is what I got by now.

I thought for years that cortisol disregulations (too high or too low) must be due to a malfuncioning of the adrenal glands. I walked on this pathway for very long, thinking that the disregulations of my blood glucose, of triglycerides and of cortisol must be due to the adernal malfunction, more specifically what some name ADRENAL FATIGUE.

Only lately I wanked up on the HPA axis, in order to realize that a disregulation in the production of the CRH hormone from the brain hypothalamus can disregulate the HPA axis, the cortizol production and gives a chain of reactions in the body, from immunocompetence to glucose disregulations.

Cadidiasis patients may have a deffect in the CRH gene, which I am not sure that can be fixed. If aquired, possibly it can be fixed.

Sleep deprivation and stress both increase CRH levels. HPA axis, according to some medical sciencemen, may become irresponsive to CRH after some time when CRH is continuously at abnormally high levels. For now Iam not sure about the truth of this assertion.

CRH ust therefore be controlled either by decreasing CRH prodution itself or by targeting the CRH receptors, which is harder to achieve.

Benzodiazepines have the property of attenuating the pituitary-adrenal responses to corticotrophin-releasing hormone in healthy subjects, but not in those with Cushing's Syndrome.

Alprazolam attenuates vasopressin-stimulated adrenocorticotropin and cortisol release: evidence for synergy between vasopressin and corticotropin-releasing hormone in humans.

Alprazolam (APZ), a triazolobenzodiazepine with unique clinical utility, has potent inhibitory effects on the human hypothalamic- pituitary-adrenal axis. Because APZ inhibits CRH secretion from isolated rat hypothalami and inhibits the probable CRH-mediated effect of naloxone on ACTH release, it is likely APZ acts as an inhibitor of hypothalamic CRH release in humans.

Chronic elevated CRH might blunt the CRH receptors and these might become irresponsive. Adjusting CRH levels might eventually be a way of conserving the CRH receptors and hopefully to restore their previous ability to work properly.

This might be achieved with CHR inhibitors aka benzodiazepines.