Nitric oxide and oxyradical production by brain mitochondria after chlorpromazine treatment

LORES ARNAIZ, SILVIA; DAMICO, GABRIELA; BUSTAMANTE, JOANITA; CARDILLO, ALEJANDRA BEATRIZ; BOVERIS, ALBERTO

Buenos Aires

Congreso; Joint Meeting Eighteenth Biennial Meeting of the International Society for Neurochemistry (ISN) and Thirty-Second Annual Meeting of the American Society for Neurochemistry (ASN); 2001

Recent studies have shown that nitric oxide (NO) can be an important mediator of pathogenic nervous tissue damage and may play a role in neurodegenerative disorders, as a mediator of oxygen toxicity in CNS. In this study of acute chlorpromazine (CPZ) toxicity NO and superoxide (O2-) production rates were measured in sub-mitochondrial particles (SMP) and oxygen consumption and hydrogen peroxide (H2O2) production rate were determined in isolated brain mitochondria. CPZ treatment produced an inhibition of NO production of 58%. Incubation of brain SMP with 1-4 µM CPZ inhibited NO production in a concentration-dependent manner. Was observed am increase of malate-glutamate dependent oxygen uptake of about 45-50% both in state 4 and 3 respiration. Succinate-supported respiration (state 4) was 29% increased by CPZ treatment. O2- production rate was significantly decreased in brain SMP and mitochondrial H2O2 production rate was increased by 49% both in the presence of succinate-antimycin, after CPZ treatment. Western blot analysis showed that brain mitochondrial membranes from CPZ-treated mice presented decreased neuronal NO synthase content as compared with those from untreated mice. It appears that mitochondrial NO synthase can be subjected to pharmacological regulation. Our results suggest that inhibition of mitochondrial NO production, impaired oxygen consumption and enhancement of H2O2 production would contribute to acute chlorpromazine neurotoxicity.