Zn²⁺‐induced ERK activation mediates PARP‐1‐dependent ischemic‐reoxygenation damage to oligodendrocytes

Abstract

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.

Catalpol Protects Pre-Myelinating Oligodendrocytes against Ischemia-induced Oxidative Injury through ERK1/2 Signaling Pathway

“…This dual role of the ERK1/2 signaling pathway has also been observed in OLs. A rapid and transient increase in ERK1/2 phosphorylation secondary to AMPA receptor activation inhibits OL death 39, whereas delayed and sustained ERK1/2 phosphorylation following ischemia and reperfusion induces OL death 20. Herein, we found that OGD-induced activation of ERK1/2 clearly resulted in PreOL damage, because blockade of this pathway by U0126 significantly inhibited PreOL death, reduced ROS generation, and ameliorated mitochondrial dysfunction.…”

“…Oxidative stress elicited by ROS generation is often linked to activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, and cellular oxidative damage in several paradigms requires sustained ERK1/2 phosphorylation 18, 19. Recent studies have revealed that the ERK1/2 signaling pathway is activated during ischemic damage and contributes to ischemia-induced OL death 20. It has also been reported that catalpol-mediated suppression of ERK1/2 is a pivotal mechanism explaining its neuroprotection against rotenone-induced oxidative stress in mesencephalic neurons 21.…”

Autophagy Mediates Astrocyte Death During Zinc-Potentiated Ischemia–Reperfusion Injury

“…Zinc can cause hypoxic cell death through both caspase-dependent and -independent pathways [13,42,43], and it has also been reported as a factor in neuron necrosis pathway in ischemic rats [8]. Therefore, the mechanism of zinc-induced hypoxic cell death needs further investigation.…”

Prevention of cell death by the zinc ion chelating agent TPEN in cultured PC12 cells exposed to Oxygen–Glucose Deprivation (OGD)

“…In addition, other studies have also indicated that Zn 2+ plays a crucial role in subsequent neuronal death caused by hypoxia-ischemia [7]. Redundant Zn 2+ induces apoptosis of various cells such as thymocytes [8], oligodendrocyte [9] and neuron [10]. Further studies observed increases in extracellular free Zn 2+ concentrations following hypoxic-ischemic like event [11].…”