Effect of diazepam treatment and its withdrawal on pro/antioxidative processes in rat brain

Abstract

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 The total and free -SH content in the withdrawn animals increased by 46% in cerebellum with no change in the other two regions.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.