Fig. 9. Model of early and late events in oxidant-induced neuronal injury. Based on the findings in this and our previous work, the cellular and molecular signaling pathways that contribute to oxidant-induced neurotoxicity have been summarized. The “early” events (left panel) in DTDP toxicity include the rapid loss of zinc homeostasis within 10 min of exposure to DTDP (Aizenman et al., 2000), a primary oxidative cell injury resulting in a rapid increase in p38 phosphorylation within 30 min of oxidant exposure, and then subsequent DNA damage within 3 hr of DTDP treatment (Aizenman et al., 2000). p38 activation can be blocked by the zinc chelator TPEN and, to some degree, by the free radical spin trap, PBN. Also by 3 hr, enhanced activation of TEA-sensitive potassium channels associated with apoptosis can be observed. p38 is directly responsible for the loss of intracellular potassium because the p38 inhibitor SB 239063 can attenuate channel activity, whereas potassium channel blockers have a very small effect on p38 activity. The “late” events (right panel) in this cascade likely include energetic dysfunction brought on by zinc dysregulation (Skulachev et al., 1967; for review, see Weiss et al., 2000), NADH depletion, and, ultimately, caspase activation within 7 hr. Blockade of any of these events with compounds such as niacinamide, benzamide, and peptide and nonpeptide caspase inhibitors provides substantial neuroprotection.