title: 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.
authors.affiliation: Departamento de Neurociencias, Centro de Investigaciones Biomédicas en Red, Universidad del País Vasco, Leioa, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Domercq
authors.forename: Susana
authors.initials: S
authors.lastname: Mato
authors.forename: Federico N
authors.initials: FN
authors.lastname: Soria
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Sánchez-gómez
authors.forename: Elena
authors.initials: E
authors.lastname: Alberdi
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D015032:Zinc / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose; D015032:Zinc; D002118:Calcium