Intracellular zinc release, 12-lipoxygenase activation and MAPK dependent neuronal and oligodendroglial death

Abstract

Zinc translocation from presynaptic nerve terminals to postsynaptic neurons has generally been considered the critical step leading to the accumulation of intracellular free zinc and subsequent neuronal injury. Recent evidence, however, strongly suggests that the liberation of zinc from intracellular stores upon oxidative and nitrative stimulation contributes significantly to the toxicity of this metal not only to neurons, but also to oligodendrocytes. The exact cell death signaling pathways triggered by zinc are beginning to be deciphered. In this review, we describe how the activation of 12-lipoxygenase and mitogen-activated protein kinase (MAPK) contribute to the toxicity of liberated zinc to neurons and oligodendrocytes.

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.

Figure 2

Pathway of peroxynitrite-induced toxicity to mature oligodendrocytes. Peroxynitrite triggers zinc release from metallothionein and/or mitochondria either directly or indirectly via the conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG). Zinc induces ERK1/2 phosphorylation, which may be due partially to the inhibition of MKP activity. In contrast to neurons, ERK1/2 phosphorylation occurs upstream of 12-LOX in mature oligodendrocytes. ROS generated from 12-LOX activation and mitochondria are toxic to mature oligodendrocytes.