Role of nitric oxide overproduction in development of Alzheimer's disease and possibility of its prevention using adaptation to hypoxia

Abstract

Excessive nitric oxide (NO) production in brain has been implicated in development and progression of neurodegenerative diseases including Alzheimer’s disease (AD). Direct neurotoxic effects of excessive NO are mediated by mitochondrial dysfunction and ATP depletion, apoptosis of neural cells, excitotoxicity, nitration or oxidation of proteins resulting from NO-mediated formation of reactive nitrogen and oxygen species, and damage and dysfunction of microvascular cells with ensuing disorders of cerebral circulation. Recent studies have demonstrated that adaptation to intermittent hypoxia can prevent NO overproduction, excessive protein nitration, and increased expression of all NO synthase isoforms in brain of rats with experimental AD. This prevention of NO overproduction is associated with reduced cognitive disorders, diminished loss of brain neurons, less endothelial dysfunction, and increased cerebral vascular density. Possible mechanisms for the restriction of NO overproduction by adaptation to hypoxia include 1) limitation of NO production due to inadequate NOS substrate O2; 2) moderate increase in NO level, which provides NOS feedback inhibition; 3) O2 modulation of the feedback inhibition; 4) restriction of oxidative stress; and 5) binding excessive NO to NO stores. Therefore, approaches of adaptive medicine can be used as a strategy to improve neuronal self-defense mechanisms which suppress progression towards AD.