Oxidative stress in neurodegeneration: mechanisms and therapeutic perspectives

Neural tissue is especially sensitive to oxidative stress, which is considered a prominent factor in both acute and chronic neurodegenerative diseases and traumatic brain insults. On this basis, therapeutical strategies centered on antioxidants and on drugs able to scavenge excess free radicals and to re-establish the redox equilibrium, have been proposed for treatment of several brain pathologies. The present paper shortly summarizes the main sources of free radical production in the brain and reviews some of the recent data on mechanisms of cellular transduction through which free radicals are believed to damage cells and, eventually, to bring them to death. Some of the most promising therapeutical perspectives for treatment of oxidative stress in neurodegeneration, are then considered. Their choice is the result of a selection, that is unavoidably due to the enormous amount of the literature data, based on personal evaluation as well as on the personal experimental experience of the author. Four main categories of possible therapeuticals are considered: inhibitors of antioxidant enzymes, endogenous antioxidants and their precursors, vitamins and related compounds, other natural antioxidants from fruits and vegetables. Some theoretical and practical issues relevant to the adoption of antioxidant therapies for neurodegeneration are highlited, with particular reference to the fact that a basal production of free radicals must be maintained in the brain due to the host of essential cellular functions subserved by them. In this connection, it seems advisable that future antioxidant strategies for neurodegeneration are based on mixtures of agents able to modulate multiple mechanisms of free radical production and scavenging, without dangerously hampering essential physiological defense based on free radical cellular signaling.