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Inhibition of glutamate release by delaying ATP fall accounts for neuroprotective effects of antioxidants in experimental stroke
Author(s) -
Hurtado Olivia,
De Cristóbal Javier,
Sánchez Verónica,
Lizasoain Ignacio,
Cárdenas Antonio,
Pereira Marta P.,
Colado M. Isabel,
Leza Juan C.,
Lorenzo Pedro,
Moro María A.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-1086fje
Subject(s) - neuroprotection , glutamate receptor , glutathione , pharmacology , ischemia , mitochondrion , oxidative phosphorylation , reactive oxygen species , chemistry , mitochondrial respiratory chain , respiratory chain , biochemistry , medicine , enzyme , receptor
Excitotoxic neuronal injury related to excessive glutamate release is believed to play a key role in the pathogenesis of focal cerebral ischemia. Reversal of neuronal glutamate transporters caused by ATP fall and subsequent imbalance of membrane ionic gradients accounts for most glutamate release after cerebral ischemia. ATP synthesis from oxidative phosphorylation derives from the coupled functioning of the mitochondrial respiratory chain (MRC) and the ATP synthase; interestingly, the MRC is one of the main sites of cellular reactive oxygen species (ROS) generation even in physiological circumstances. Hence, we have studied the effect of the antioxidants glutathione, superoxide dismutase, and α‐tocopherol on infarct outcome, brain ATP, and glutamate levels after permanent middle cerebral artery occlusion (MCAO) in Fischer rats; we have also characterized the actions of antioxidants on MRC complexes. Our results show that intraperitoneal administration of antioxidants 2 h before MCAO enhances ATP synthesis and causes a neuroprotective effect concomitant to inhibition of ischemia‐induced increase in brain glutamate. Antioxidants also increased mitochondrial ATP and MRC complex I–III activity and respiration, suggesting that these actions are due to removal of the inhibition caused by endogenous ROS on MRC. These findings may possess important therapeutic repercussions in the management of ischemic stroke.