Nitric oxide inactivation mechanisms in the brain: role in bioenergetics and neurodegeneration.

During the last decades nitric oxide ((•)NO) has emerged as a critical physiological signaling molecule in mammalian tissues, notably in the brain. (•)NO may modify the activity of regulatory proteins via direct reaction with the heme moiety, or indirectly, via S-nitrosylation of thiol groups or nitration of tyrosine residues. However, a conceptual understanding of how (•)NO bioactivity is carried out in biological systems is hampered by the lack of knowledge on its dynamics in vivo. Key questions still lacking concrete and definitive answers include those related with quantitative issues of its concentration dynamics and diffusion, summarized in the how much, how long, and how far trilogy. For instance, a major problem is the lack of knowledge of what constitutes a physiological (•)NO concentration and what constitutes a pathological one and how is (•)NO concentration regulated. The ambient (•)NO concentration reflects the balance between the rate of synthesis and the rate of breakdown. Much has been learnt about the mechanism of (•)NO synthesis, but the inactivation pathways of (•)NO has been almost completely ignored. We have recently addressed these issues in vivo on basis of microelectrode technology that allows a fine-tuned spatial and temporal measurement (•)NO concentration dynamics in the brain.