Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders

The term “nitrosative stress” is used to indicate the cellular damage elicited by reactive nitrogen species (RNS), including nitric oxide (NO) and its congeners peroxynitrite (OONO−), N2O3, nitroxyl anion, and nitrosonium. Nitrosative stress has been implicated in the pathogenesis of neurodegenerative disorders. In this chapter, the importance of nitrosative stress in the pathogenesis of brain aging and neurodegenerative disorders as well as the key role played by HO-1 in modulating the onset and progression of Alzheimer's disease (AD) and Parkinson's disease (PD) is discussed. The mechanism(s) by which nitrosative stress is involved in the pathogenesis of neurodegenerative diseases is manifold. In fact, NO itself has been shown to regulate selected proteins—such as parkin, metalloproteinase-9 (MMP-9), and glyceraldehyde-3-phosphate dehydrogenase (GADPH)—via an S-nitrosylation reaction, thereby triggering the onset and progression of PD and other neurodegenerative disorders. On the other hand, NO can react with reactive oxygen species (ROS), in particular superoxide, derived from mitochondrial impairment and form peroxynitrite, which nitrosates proteins and forms 3-NT-modified proteins, which cause an impairment in cellular metabolic pathways and therefore cell death. Therefore, it is possible to hypothesize that drugs which are able to counteract iNOS induction and therefore excess NO formation can be very useful in limiting the consequences of oxidative and nitrosative stress associated with neurodegenerative disorders. Furthermore, the compelling evidence of the vitagene network as a defense system operating in the brain during times of oxidative and nitrosative stress opens new perspectives in the treatment of neurodegenerative diseases.