Perspectives on the development of antioxidant antiepileptogenic agents

Epilepsy is a chronic disorder of abnormal electrical activity in the brain characterized by recurrent unprovoked seizures. Currently used pharmaceutical agents do not treat the underlying disease process, and a significant proportion of epileptic patients are refractory to current therapies. Therefore there is a strong need for additional therapeutic agents, especially those that address the underlying disease process of epileptogenesis. The redox potential of cells is maintained by an appropriate balance between pro- and anti-oxidative molecules; oxidative stress and increases in toxic reactive oxygen species occur when this balance shifts towards oxidation. Neural tissues are especially sensitive to oxygen levels, and oxidative stress is thought to be involved in epileptogenesis. Increases in reactive oxygen species occur in response to sustained neuronal electrical activity and seizures. Therefore antioxidants have been suggested as therapeutic design strategies for the treatment and modulation of epilepsy. This minireview focuses on several key antioxidants and agents involved in defending against oxidative stress that may be targets for new antiepileptogenic drug design, including directacting antioxidants, Nrf2-activating agents, and prolyl-4-hydroxylase inhibitors. A description of the necessary physicochemical properties and a summary of animal models that are thought to be useful for developing antiepileptogenic agents are presented.