Pro and antioxidant responses to repeated administration of diazepam in rat brain

The role of pro/antioxidative processes during a low, subtoxic dose schedul e of diazepam (3 mg/kg/day i.p.) for 7 days and its withdrawal in subcellul ar preparations of rat brain regions was studied in detail. The results ind icated heterogeneity in the regional responses as well as in subcellular co mpartments. After 7 days of exposure to the drug, a decrease in the Mn-SOD activity was observed in the 3 regions studied while a significant increase in Cu/Zn-SOD activity was seen in cerebellum (CBL) and brain stem (BS) alo ng with that of mitochondrial glutathione reductase. The post-mitochondrial fraction (PMF) showed a significant increase in GR activity in cerebrum. E nhancement of total and free thiol levels was observed in cerebrum and cere bellum whereas in BS free thiols were not enhanced. It was interesting to n ote that in the animals withdrawn from the drug and sacrificed after an int erval of 7 days, the level of TBARS showed a highly significant increase in mitochondria of CB and CBL and 89% increase in BS. Similar trend was obser ved in the post-mitochondrial fractions of all the 3 regions whereas the ac tivity of isozymes of SOD decreased (p < 0.001) in CBL and BS and to a less er extent in CB. The GR activity was significantly decreased only in the mi tochondria of cerebrum with a 34% rise in cerebellum and no change in BS. T he PMFs showed a decrease in CB and CBL but a 20% rise in BS. Thus, the dat a show modulation of antioxidant responses during short-term administration of diazepam, and a lowering of peroxidative decomposition of polyunsaturat ed fatty acids of membranes. However, after withdrawal of the drug, PUFAs w ere found to be more vulnerable to peroxidative decomposition and changes i n the antioxidant defenses were also observed, which did not come back to n ormal level during the study.