Novel targets for therapeutic intervention against ischemic brain injury.

Ischemic stroke is a major health care problem worldwide, and the mechanisms that lead to ischemic brain injury are not completely defined. In the past few years, the identification of many molecules that participate in neuronal death and particularly in apoptosis, has shed light on the development of neuroprotective therapy. Glycine site antagonism of N-methyl-D-aspartate (NMDA) receptors may offer an alternative means to a blockade of glutamate neurotoxicity, which lacks most side effects associated with competitive and noncompetitive NMDA receptor antagonists. Inflammatory processes executed by some proinflammatory molecules contribute to secondary brain injury. Neutral protease calpain is capable of degrading critical cytoskeletal and regulatory proteins, mainly causing postischemic neuronal necrosis. Caspases, a family of cysteine proteases, are at the heart of the apoptotic pathway. Severe DNA damage induced by oxidative stress or apoptotic stimuli activates poly(ADP-ribose) polymerase, causing a rapid depletion of nuclear NAD pools, cellular energy, and thiols. Inhibition of these inducible molecules is expected to achieve effective neuroprotection without serious side effects because the molecules seem relatively unimportant in normal neurotransmission. In the future, the efficacy of these novel strategies should be confirmed in larger study populations, individually and in combinations, before considering clinical application.