Nitric oxide, mitochondria and neurological disease

Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurological disor ders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke and amyotrophic lateral sclerosis. There is also a growing body of evidence to implicate excessive or inappropriate generation of nitric oxide (NO) in these disorders. It is now well documented that NO and its toxic m etabolite, peroxynitrite (ONOO-), can inhibit components of the mitochondri al respiratory chain leading, if damage is severe enough, to a cellular ene rgy deficiency state. Within the brain, the susceptibility of different bra in cell types to NO and ONOO- exposure may be dependent on factors such as the intracellular reduced glutathione (GSH) concentration and an ability to increase glycolytic flux in the face of mitochondrial damage. Thus neurone s, in contrast to astrocytes, appear particularly vulnerable to the action of these molecules. Following cytokine exposure, astrocytes can increase NO generation, due to de novo synthesis of the inducible form of nitric oxide synthase (NOS). Whilst the NO/ONOO- so formed may not affect astrocyte sur vival, these molecules may diffuse out to cause mitochondrial damage, and p ossibly cell death, to other cells, such as neurones, in close proximity. E vidence is now available to support this scenario for neurological disorder s, such as multiple sclerosis. In other conditions, such as ischaemia, incr eased availability of glutamate may lead to an activation of a calcium-depe ndent nitric oxide synthase associated with neurones. Such increased/inappr opriate NO formation may contribute to energy depletion and neuronal cell d eath. The evidence available for NO/ONOO--mediated mitochondrial damage in various neurological disorders is considered and potential therapeutic stra tegies are proposed. (C) 1999 Elsevier Science B.V. All rights reserved.