NITRIC OXIDE-MEDIATED MITOCHONDRIAL DAMAGE IN THE BRAIN - MECHANISMS AND IMPLICATIONS FOR NEURODEGENERATIVE DISEASES

Within the CNS and under normal conditions, nitric oxide ((NO)-N-.) ap pears to be an important physiological signalling molecule. Its abilit y to increase cyclic GMP concentration suggests that (NO)-N-. is impli cated in the regulation of important metabolic pathways in the brain. Under certain circumstances (NO)-N-. synthesis may be excessive and (N O)-N-. may become neurotoxic. Excessive glutamate-receptor stimulation may lead to neuronal death through a mechanism implicating synthesis of both (NO)-N-. and superoxide (O-2(.)-) and hence peroxynitrite (ONO O-) formation. In response to lipopolysaccharide and cytokines, glial cells may also be induced to synthesize large amounts of (NO)-N-., whi ch may be deleterious to the neighbouring neurones and oligodendrocyte s. The precise mechanism of (NO)-N-. neurotoxicity is not fully unders tood. One possibility is that it may involve neuronal energy deficienc y. This may occur by ONOO- interfering with key enzymes of the tricarb oxylic acid cycle, the mitochondrial respiratory chain, mitochondrial calcium metabolism, or DNA damage with subsequent activation: of the e nergy-consuming pathway involving poly(ADP-ribose) synthetase. Possibl e mechanisms whereby ONOO- impairs the mitochondrial respiratory chain and the relevance for neurotoxicity are discussed. The intracellular content of reduced glutathione also appears important in determining t he sensitivity of cells to ONOO- production. It is concluded that neur otoxicity elicited by excessive (NO)-N-. production may be mediated by mitochondrial dysfunction leading to an energy deficiency state.