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

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