The bioactivity of neuronal-derived nitric oxide in aging and neurodegeneration: Switching signaling to degeneration

The small and diffusible free radical nitric oxide (•NO) has fascinated biological and medical scientists since it was promoted from atmospheric air pollutant to biological ubiquitous signaling molecule. Its unique physical chemical properties expand beyond its radical nature to include fast diffusion in aqueous and lipid environments and selective reactivity in a biological setting determined by bioavailability and reaction rate constants with biomolecules. In the brain, •NO is recognized as a key player in numerous physiological processes ranging from neurotransmission/neuromodulation to neurovascular coupling and immune response. Furthermore, changes in its bioactivity are central to the molecular pathways associated with brain aging and neurodegeneration. The understanding of •NO bioactivity in the brain, however, requires the knowledge of its concentration dynamics with high spatial and temporal resolution upon stimulation of its synthesis. Here we revise our current understanding of the role of neuronal-derived •NO in brain physiology, aging and degeneration, focused on changes in the extracellular concentration dynamics of this free radical and the regulation of bioenergetic metabolism and neurovascular coupling. [Display omitted] •Changes in the bioactivity of •NO are central to the molecular pathways associated with brain aging and neurodegeneration.•Bioactivity of •NO is shaped by the redox milieu in cells and tissues, which impacts neurometabolism, neurovascular coupling and neuroinflammation.••NO concentration Dynamics in brain tissue can be monitoried using electrochemical methods coupled to microelectrodes.