Figure 1

Oxidative or nitrative stress-induced neuronal death pathways. Peroxynitrite or oxidative stressors (for example, DTDP, MIT) cause zinc release from metallothionein and/or mitochondria either directly or indirectly via the conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG). Zinc activates 12-LOX and causes neuronal death via activation of p38 or ERK1/2. Phosphorylation of p38 results in caspase-dependent apoptosis, which is mediated in part by phosphorylation of the Kv2.1 potassium channel and subsequent K ± efflux. Phosphorylation of ERK1/2, which is downstream of 12-LOX activation and ERK1/2 directed phosphatase (MKP) inhibition, causes NADPH oxidase activation and ROS generation. ROS, which are also generated from activation of 12-LOX and from mitochondria, activate PARP leading to ATP depletion and caspase-independent neuronal death.