Science; 2/20/2004; Chong, Lisa D. Science 02-20-2004 Excessive nitric oxide (NO) and the release of zinc from intracellular stores have been linked to neuronal death associated with stroke and some neurodegenerative diseases. The mechanisms that mediate the neurotoxic effects have not been clear. Bossy-Wetzel et al. found that zinc is an important component of the NO neurotoxicity pathway. Increased intracellular zinc within mitochondria was observed in cultured cerebrocortical neurons exposed to NO. A free-radical scavenger blocked this effect. Zinc blocked respiration in isolated mitochondria, suggesting that this organelle is a key target of zinc-mediated toxicity. A zinc chelator blocked NO-induced activation of p38 mitogen-activated protein kinase (MAPK), a critical signaling molecule in the NO response pathway. NO exposure was also associated with potassium efflux and cell shrinkage, a morphological change characteristic of neuronal apoptosis. Treatment of neurons with a potassium channel antagonist, a zinc chelator, a reactive oxygen species (ROS) scavenger, or an inhibitor of p38 MAPK decreased NO-mediated neuronal cell death. Thus it appears that NO triggers zinc-mediated inhibition of mitochondrial function via an increase in ROS production. ROS then reacts with NO to activate p38 MAPK, which could then alter potassium channel function, causing progressive cell death. -- LDC Neuron 41, 351 (2004). Copyright © 2004 by the American Association for the Advancement of Science