In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 9 ( 2012-02-29), p. 3235-3244
Abstract:
Oxidative stress and Ca 2+ toxicity are mechanisms of hypoxic–ischemic (HI) brain injury. This work investigates if partial inhibition of mitochondrial respiratory chain protects HI brain by limiting a generation of oxidative radicals during reperfusion. HI insult was produced in p10 mice treated with complex I (C-I) inhibitor, pyridaben, or vehicle. Administration of P significantly decreased the extent of HI injury. Mitochondria isolated from the ischemic hemisphere in pyridaben-treated animals showed reduced H 2 O 2 emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to the Ca 2+ -triggered opening of the permeability transition pore. A protective effect of pyridaben administration was also observed when the reperfusion-driven oxidative stress was augmented by the exposure to 100% O 2 which exacerbated brain injury only in vehicle-treated mice. In vitro , intact brain mitochondria dramatically increased H 2 O 2 emission in response to hyperoxia, resulting in substantial loss of Ca 2+ buffering capacity. However, in the presence of the C-I inhibitor, rotenone, or the antioxidant, catalase, these effects of hyperoxia were abolished. Our data suggest that the reperfusion-driven recovery of C-I-dependent mitochondrial respiration contributes not only to the cellular survival, but also causes oxidative damage to the mitochondria, potentiating a loss of Ca 2+ buffering capacity. This highlights a novel neuroprotective strategy against HI brain injury where the major therapeutic principle is a pharmacological attenuation, rather than an enhancement of mitochondrial oxidative metabolism during early reperfusion.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.6303-11.2012
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2012
detail.hit.zdb_id:
1475274-8
SSG:
12
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