Effect of chronic treatment of carvedilol on oxidative stress in an intracerebroventricular streptozotocin induced model of dementia in rats.
ABSTRACT Oxidative stress is emerging as an important issue in the pathogenesis of dementia. This study was conducted to investigate the possible neuroprotective effects of carvedilol against streptozotocin induced behavioural alterations and oxidative damage in rats.
An intracerbroventricular cannula was implanted in the lateral ventricles of male Wistar rats. Various behavioural (locomotor activity, Morris water maze task) and biochemical parameters (lipid peroxidation, nitrate concentration, catalase, acetylcholinesterase, reduced glutathione and protein) were assessed.
Intracerebroventricular administration of streptozotocin caused a significant memory deficit as evaluated in the Morris water maze task paradigms, and caused marked oxidative damage as indicated by significant increases in malondialdehyde and nitrite levels, and depletion of superoxide dismutase, catalase and reduced glutathione levels. It also caused a significant increase in acetylcholinesterase activity. Chronic administration of carvedilol (1 and 2 mg/kg, i.p.) for a period of 25 days starting 4 days before streptozotocin administration resulted in an improvement in memory retention, and attenuation of oxidative damage and acetylcholinesterase activity.
This study demonstrates the effectiveness of carvedilol in preventing cognitive deficits as well as the oxidative stress caused by intracerbroventicular administration of streptozotocin in rats. Carvedilol may have potential in the treatment of neurodegenerative diseases.
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ABSTRACT: Accompanying the autoxidation of hydroxylamine at pH 10.2, nitroblue tetrazolium was reduced and nitrite was produced in the presence of EDTA. The rate of autoxidation was negligible below pH 8.0, but sharply increased with increasing pH. The reduction of nitroblue tetrazolium was inhibited by superoxide dismutase, indicating the participation of superoxide anion radical in the autoxidation. Hydrogen peroxide stimulated the autoxidation and superoxide dismutase inhibited the hydrogen peroxide-induced oxidation, results which suggest the participation of hydrogen peroxide in autoxidation and in the generation of superoxide radical. An assay for superoxide dismutase using autoxidation of hydroxylamine is described.Archives of Biochemistry and Biophysics 03/1978; 186(1):189-95. · 3.37 Impact Factor
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ABSTRACT: 1. Tardive dyskinesia (TD), a syndrome of potentially irreversible, involuntary hyperkinetic disorder occurring in 20 - 40% of the patient population undergoing chronic neuroleptic treatment is a major limitation of neuroleptic therapy. 2. Oxidative stress and products of lipid peroxidation are implicated in the pathophysiology of various neurological disorders including tardive dyskinesia. 3. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats known as vacuous chewing movements (VCMs). Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. 4. All the antipsychotics were administered i.p. once daily for 21 days, whereas carvedilol (also i.p.) was administered twice daily. Rats chronically treated with haloperidol (1.0 mg kg(-1)) or chlorpromazine (5 mg kg(-1)) but not clozapine (2 mg kg(-1)) significantly developed vacuous chewing movements and tongue protrusions. Carvedilol dose dependently (0.5 - 2 mg kg(-1)) reduced the haloperidol or chlorpromazine-induced vacuous chewing movements and tongue protrusions. 5. Biochemical analysis revealed that chronic haloperidol or chlorpromazine but not clozapine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the forebrains of rats. Chronic haloperidol or chlorpromazine but not clozapine treated rats showed decreased forebrain levels of antioxidant defence enzymes, superoxide dismutase (SOD) and catalase. 6. Co-administration of carvedilol (0.5-2 mg kg(-1)) significantly reduced the lipid peroxidation and restored the decreased glutathione levels by chronic haloperidol or chlorpromazine treatment. Co-administration of carvedilol (1-2 mg kg(-1)) significantly reversed the haloperidol or chlorpromazine-induced decrease in forebrain SOD and catalase levels in rats. However, lower dose of carvedilol (0.5 mg kg(-1)) failed to reverse chronic haloperidol or chlorpromazine-induced decrease in forebrain SOD and catalase levels. 7. The major findings of the present study suggest that oxidative stress might play a significant role in neuroleptic-induced orofacial dyskinesia. In conclusion, carvedilol could be a useful drug for the treatment of neuroleptic-induced orofacial dyskinesia.British Journal of Pharmacology 06/2002; 136(2):193-200. · 5.07 Impact Factor
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ABSTRACT: The ability of the nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester (L-NAME), to modulate the attenuating effects of neurosteroids on the aging- and NMDA receptor antagonist dizocilpine-induced learning impairment, was tested in mice using two different behavioral models of long-term memory. The performance of aged mice (16 months old) in step-down type of passive-avoidance and elevated plus-maze paradigms was significantly impaired compared to that of young mice (3 months old). Neurosteroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), at 1-20 mg/kg, s.c., significantly improved the passive-avoidance and plus-maze performances in aged mice. Neurosteroids PS and DHEAS, at doses 1-20 mg/kg, s.c., significantly attenuated dizocilpine (0.1 mg/kg, i.p.)-induced amnesia, without producing any promnestic effects alone in adult mice. In both cognitive tasks, the effects exhibited by the neurosteroids tested had a bell-shaped curve. Preadministration of L-NAME (10 and 20 mg/kg, i.p.), at doses that did not disrupt cognition alone in either young or aged mice, significantly blocked the beneficial and antiamnesic effects of neurosteroids PS (5 mg/kg) and DHEAS (10 mg/kg). A selective action of L-NAME on the effects of neurosteroids was indicated, since the effects of L-NAME were completely reversed by L-arginine (300 mg/kg, i.p.), a competitive substrate for NO synthase. Neither L-NAME nor L-arginine alone affected the antinociception, locomotor activity or rota-rod performance of young or aged mice. These observations suggest that a NO-dependent mechanism may be involved in the beneficial and antiamnesic effects of neurosteroids PS and DHEAS on the aging- and dizocilpine-induced impairment of learning and memory processes.Brain Research 08/1998; 799(2):215-29. · 2.88 Impact Factor