Nitric Oxide-Mediated Mitochondrial Damage in the Brain: Mechanisms and Implications for Neurodegenerative Diseases

Authors


Address correspondence and reprint requests to Dr. S. J. R. Heales at Department of Clinical Biochemistry, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, U.K.

Abstract

Abstract: Within the CNS and under normal conditions, nitric oxide (NO) appears to be an important physiological signalling molecule. Its ability to increase cyclic GMP concentration suggests that NO is implicated in the regulation of important metabolic pathways in the brain. Under certain circumstances NO synthesis may be excessive and NO may become neurotoxic. Excessive glutamate-receptor stimulation may lead to neuronal death through a mechanism implicating synthesis of both NO and superoxide (O2•−) and hence peroxynitrite (ONOO) formation. In response to lipopolysaccharide and cytokines, glial cells may also be induced to synthesize large amounts of NO, which may be deleterious to the neighbouring neurones and oligodendrocytes. The precise mechanism of NO neurotoxicity is not fully understood. One possibility is that it may involve neuronal energy deficiency. This may occur by ONOO interfering with key enzymes of the tricarboxylic acid cycle, the mitochondrial respiratory chain, mitochondrial calcium metabolism, or DNA damage with subsequent activation of the energy-consuming pathway involving poly(ADP-ribose) synthetase. Possible 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 the sensitivity of cells to ONOO production. It is concluded that neurotoxicity elicited by excessive NO production may be mediated by mitochondrial dysfunction leading to an energy deficiency state.

Abbreviations used: eNOS, endothelial nitric oxide synthase; GSH, glutathione; IFN, interferon; iNOS, inducible nitric oxide synthase; NMDA, N-methyl-d-aspartate; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; NOS, nitric oxide synthase; O2•−, superoxide; ONOO, peroxynitrite; TMPD, tetramethylphenylenediamine.

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