Much of the cell death following episodes of
anoxia and
ischemia in the mammalian central nervous system has been attributed to extracellular accumulation of
glutamate and
ATP, which causes a rise in [Ca(2+)](i), loss of mitochondrial potential, and cell death. However, restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury (the
oxygen paradox). Herein we describe a novel signaling pathway that is activated during
ischemia-like conditions (
oxygen and
glucose deprivation; OGD) and contributes to
ischemia-induced oligodendroglial cell death. OGD induced a retarded and sustained increase in
extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation after restoring
glucose and O(2) (reperfusion-like conditions). Blocking the ERK1/2 pathway with the
MEK inhibitor
UO126 largely protected oligodendrocytes against ischemic insults. ERK1/2 activation was blocked by the high-affinity Zn(2+)
chelator TPEN, but not by antagonists of
AMPA/
kainate or P2X7 receptors that were previously shown to be involved in ischemic oligodendroglial cell death. Using a high-affinity Zn(2+) probe, we showed that
ischemia induced an intracellular Zn(2+) rise in oligodendrocytes, and that incubation with
TPEN prevented mitochondrial depolarization and ROS generation after
ischemia. Accordingly, exposure to
TPEN and the
antioxidant Trolox reduced
ischemia-induced oligodendrocyte death. Moreover,
UO126 blocked the
ischemia-induced increase in poly-[ADP]-ribosylation of
proteins, and the
poly[ADP]-ribose polymerase 1 (PARP-1) inhibitor DPQ significantly inhibited
ischemia-induced oligodendroglial cell death-demonstrating that PARP-1 was required downstream in the Zn(2+)-ERK oligodendrocyte cell death pathway. Chelation of cytosolic Zn(2+), blocking ERK signaling, and
antioxidants may be beneficial for treating CNS white matter
ischemia-reperfusion injury. Importantly, all the inhibitors of this pathway protected oligodendrocytes when applied after the ischemic insult.