Effect of Withania somnifera root extract on reserpine-induced orofacial dyskinesia and cognitive dysfunction.

Tardive dyskinesia is one of the major side effects of long-term neuroleptic treatment. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Oxidative stress and products of lipid peroxidation are implicated in the pathophysiology of tardive dyskinesia. Repeated treatment with reserpine (1.0 mg/kg) on alternate days for a period of 5 days (days 1, 3 and 5) significantly induced vacuous chewing movements and tongue protrusions in rats. Chronic treatment with Withania somnifera root extract (Ws) for a period of 4 weeks to reserpine treated animals significantly and dose dependently (50 and 100 mg/kg) reduced the reserpine-induced vacuous chewing movements and tongue protrusions. Reserpine treated animals also showed poor retention of memory in the elevated plus maze task paradigm. Chronic Ws administration significantly reversed reserpine-induced retention deficits. Biochemical analysis revealed that chronic reserpine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the brains of rats. Chronic reserpine treated rats showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD) and catalase. Chronic administration of Ws root extract dose dependently (50 and 100 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased glutathione levels by chronic reserpine treatment. It also significantly reversed the reserpine-induced decrease in brain SOD and catalase levels in rats. The major findings of the present study indicate that oxidative stress might play an important role in the pathophysiology of reserpine-induced abnormal oral movements. In conclusion, Withania somnifera root extract could be a useful drug for the treatment of drug-induced dyskinesia.

PASS assisted search and evaluation of some azetidin-2-ones as C.N.S. active agents.

PURPOSE: The present study evaluates some azetidin-2-ones derivatives for their central nervous system (CNS) modulating activities. The compounds were chosen from a series (5a-o) which were previously synthesized and evaluated for hypolipidemic and antihyperglycemic activity based on the predictions made by the computer software "Prediction of Activity Spectra for Substances (PASS)". MATERIAL AND METHODS: The test compounds were predicted to have a variety of biological activities but those with the best potential for CNS modulating activity were selected for evaluation of a particular CNS activity as 5a for anti-anxiety, 5b, 5n and 5j for nootropic activity and compound 5c anti-catatonic and anti-dyskinetic activities. Test compound 5a was evaluated for anti-anxiety activity in mirrored chamber model and for pentobarbitone induced sleep potentiation in mice. Test compounds 5b, 5n and 5j were evaluated for nootropic activity in mice by examining the effect on transfer latency on elevated plus maze (EPM) in mice and compound 5c was tested for anti-catatonic activity in perphenazine-induced catatonia and anti-dyskinetic effects in reserpine induced orofacial dyskinesia in rats, respectively. RESULTS AND DISCUSSION: The test compound 5a showed significant anxiolytic activity in the mirror chamber paradigm and showed potentiation of the pentobarbitone-induced hypnosis, which was comparable to diazepam. The nootropic activity of compounds 5b, 5n and 5j were found to be significant in elevated and maze test. The test compound 5c significantly prevented the perphenazine-induced catalepsy in a dose dependent manner. Potentiation of anti-catatonic effect of sub-effective dose of L-dopa and reversal of sulpiride-induced catalepsy was also observed by compound 5c. It indicated that the test compound might be showing anticatatonic effect by dopaminergic stimulation probably through D2 dopaminergic receptors. Compound 5c significantly reduced the vacuous chewing movements, tongue protrusions and jaw tremors induced by reserpine. It further supports the dopaminergic agonism by the test compound as reserpine induces oral dyskinetic features by depleting catecholamine (dopamine and nor- epinephrine). CONCLUSION: It was concluded that azetidinones possess considerable CNS activities and can be further explored to find additional CNS active compounds.

Effect of Withania somnifera root extract on haloperidol-induced orofacial dyskinesia: possible mechanisms of action.

We investigated the role of oxidative stress in the pathophysiology of haloperidol (HP)-induced orofacial dyskinesia and evaluated the beneficial effect of Withania somnifera (Ws) root extract in the amelioration of HP-induced vacuous chewing movements (VCMs) and tongue protrusions in the rat model for TD. Rats were treated for 21 days with intraperitoneal HP (1 mg/kg); on day 22, VCMs and tongue protrusions were counted during a 5-minute observation period. HP-treated rats significantly developed these extrapyramidal symptoms, but coadministration of Ws root extract (100-300 mg/kg) dose-dependently reduced them. Biochemical analysis revealed that chronic HP treatment significantly increased lipid peroxidation and decreased forebrain levels of glutathione and the antioxidant defense enzymes, superoxide dismutase (SOD) and catalase. Coadministration of Ws extract significantly reduced the lipid peroxidation and significantly reversed the decrease in forebrain SOD and catalase levels but had no significant effect on the HP-induced decrease in forebrain glutathione levels. These findings strongly suggest that oxidative stress plays a significant role in HP-induced orofacial dyskinesia and that Ws could be effective in preventing neuroleptic-induced extrapyramidal side effects.

Effect of natural and synthetic antioxidants in a mouse model of chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is an illness characterized by persistent and relapsing fatigue, often accompanied by numerous symptoms involving various body systems. The etiology of CFS remains unclear; however, a number of studies have shown that oxidative stress may be involved in its pathogenesis. In the present study, a mouse model of CFS was used in which mice were forced to swim for one 6-minute session on each day for 15 days and the immobility period was recorded. There was a significant increase in immobility period in saline-treated mice on successive days. Intraperitoneal treatment with the potent antioxidants carvedilol (5 mg/kg) and melatonin (5 mg/kg) produced a significant reduction in immobility period. Similar results were observed with herbal preparations administered orally: Withania somnifera (100 mg/kg), quercetin (50 mg/kg), and St. John's wort (Hypericum perforatum L., 10 mg/kg). Biochemical analysis revealed that chronic swimming significantly induced lipid peroxidation and decreased glutathione (GSH) levels in the brains of mice. The rats also showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD), and catalase. Co-administration of antioxidants carvedilol, melatonin, W. somnifera, quercetin or St. John's wort significantly reduced lipid peroxidation and restored the GSH levels decreased by chronic swimming in mice. Further, the treatment increased levels of SOD in the forebrain and of catalase. The findings strongly suggest that oxidative stress plays a significant role in the pathophysiology of CFS and that antioxidants could be useful in the treatment of CFS.