Effect of diazepam treatment and its withdrawal on pro/antioxidative processes in rat brain.
Exploratory studies were undertaken to ascertain the role of pro/antioxidative processes during a 3 weeks administration of low sub-toxic dose of diazepam and its withdrawal. Rats were administered 3 mg/kg diazepam for 21 consecutive days and the changes observed in different regions of rat brain at the sub-cellular level. Mitochondria from cerebrum showed a 27% lowering of TBARS whereas those from cerebellum and brain stem showed 48 and 24% enhanced MDA levels respectively. No significant alteration in the SOD isozymes was observed after the dose schedule. The mitochondrial glutathione reductase (GR) activity showed a decrease in all the regions with maximum decrease (36%) recorded in brain stem while post mitochondrial fraction showed significant lowering in cerebrum (37%). Total -SH content increased in all the three regions with maximum enhancement recorded in cerebellum while the free thiol content also showed significant changes (p < 0.001) in cerebellum and brain stem. One week after the withdrawal of the drug MDA levels decreased by 38% in cerebrum and 53% each in mitochondrial fractions of cerebellum and brain stem. Regional heterogeneity in response was also observed in the post mitochondrial fractions. Mn-SOD showed lowered activity in cerebellum (22%) and in brain stem (15%). The mitochondrial GR activity decreased in all the regions being highest in cerebrum with no significant change in post mitochondrial fractions. The total and free -SH content in the withdrawn animals increased by 46% in cerebellum with no change in the other two regions. The results indicate towards lower oxidative phenomenon during 3 weeks treatment with diazepam while abrupt withdrawal causes lowering of antioxidant defenses which showed regional heterogeneity. A decrease in peroxidative decomposition of polyunsaturated fatty acids of membranes was observed on withdrawal, which could be due to stabilisation of membranes after long-term binding of diazepam.
Musavi
Sarah
S
Industrial Toxicology Research Centre, M.G Marg, Lucknow, India.
Kakkar
Poonam
P
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005980:Glutathione Reductase / Q000187:drug effects; D007274:Injections, Intraperitoneal; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000209:etiology*; D013482:Superoxide Dismutase / Q000187:drug effects; D013687:Telencephalon / Q000187:drug effects; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D014151:Anti-Anxiety Agents; D017392:Thiobarbituric Acid Reactive Substances; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D003975:Diazepam