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

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 N0 synthesis may be excessive and N0 may become neurotoxic. Excessive glutamatereceptor stimulation may lead to neuronal death through a mechanism implicating synthesis of both 'No and superoxide (02') 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(ADPribose) 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 ONOOproduction. lt is concluded that neurotoxicity elicited by excessive 'NO production may be mediated by mitochondrial dysfunction leading to an energy deficiency state.

3,4-Dihydroxyphenylacetic acid (DOPAC) modulates the toxicity induced by nitric oxide in PC-12 cells via mitochondrial dysfunctioning

“…It has been shown that under conditions of excessive or inappropriate formation NO and its derivatives may cause neuronal cell death via mechanisms involving, among others, mitochondrial dysfunction (Dawson and Dawson, 1998;Bolañ os et al, 1997;Brown, 1999).…”

Nitric oxide in brain: diffusion, targets and concentration dynamics in hippocampal subregions

“…In neurodegenerative pathologies, NO Å from the iNOS of activated astrocytes or microglia might contribute to NO Å production and inhibit persistently mitochondrial respiration in neurons (reviewed in Brown and Bal-Price, 2003). In this regard, the NO Å -dependent mitochondrial dysfunction leading to an energy deficient state may constitute a pathway driving neurodegeneration (Bolanos et al, 1997).…”

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

“…In contrast, NOS-2, originally identified in macrophages, is regulated by transcriptional induction and does not require calcium increases for activity, apparently because it has tightly bound calmodulin. All isoforms contain flavin adenine dinucleotide, flavin adenine mononucleotide, iron protoporphyrin IX, and tetrahydrobiopterin as prosthetic groups (for reviews, see (Knowles and Moncada 1994;Förstermann and Kleinert 1995;Nathan 1997 (Lipton et al 1993;Beckman and Koppenol 1996;Bolanos et al 1997).…”