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

Maria Domercq, Susana Mato, Federico N. Soria, M. Victoria Sánchez-gómez, Elena Alberdi, Carlos Matute
Glia. 2012-12-22; 61(3): 383-393
DOI: 10.1002/glia.22441

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1. Glia. 2013 Mar;61(3):383-93. doi: 10.1002/glia.22441. Epub 2012 Dec 22.

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

Domercq M(1), Mato S, Soria FN, Sánchez-gómez MV, Alberdi E, Matute C.

Author information:
(1)Departamento de Neurociencias, Centro de Investigaciones Biomédicas en Red,
Universidad del País Vasco, Leioa, Spain.

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.

Copyright © 2012 Wiley Periodicals, Inc.

DOI: 10.1002/glia.22441
PMID: 23281060 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus