Redox agents modulate neuronal activity and reproduce physiological aspects of neuronal aging

The high oxygen consumption and post-mitotic nature of the central nervous system (CNS) makes it particularly susceptible to oxidative stress, the impact of which is widely regarded as a root cause of functional impairment of the aging brain in vertebrates and invertebrates alike. Using an invertebrate model system we demonstrate that the lipid soluble antioxidant α-tocopherol can both reverse 2,2-azobis(2-methylpropion-amidine) dihydrochloride (AAPH) induced decline in excitability in young neurons as well as restore the electrical activity and excitability of aged neurons not unlike the level of their younger equivalents. Furthermore, using two analogs of α-tocopherol where either the acyl chain has been removed (Trolox™) or the hydroxyl group of the chromanol ring has been methylated we were able to assert that the restorative effect of α-tocopherol requires both insertion into the plasma membrane as well as an active OH group. Thus, our results indicate peroxidation is an important modulator of neuronal excitability as well as support the growing body of evidence suggesting α-tocopherol's actions may extend well beyond its established role as a lipid domain preventative antioxidant.