Neuroprotective properties of antioxidants in stroke correlate with their effects on ischemic release of glutamate

Abstract

Antioxidant agents potently protect against ischemic brain damage in animals, but show no clinical benefits in humans. In the present study we tested the hypothesis that potency of antioxidants in preventing pathological glutamate release can predict their ability to reduce ischemic infarction. Transient focal ischemia in rats was induced by 2‐hr occlusion of the middle cerebral artery. Antioxidants Tempol and Edaravone (500 nmols) were injected into the lateral ventricles prior to ischemia. 72 hrs later, control and antioxidant‐treated animals were evaluated for behavioral deficits and brain damage. Tempol, but not Edaravone, reduced infarction volumes by ~60% and improved neurological outcomes. In parallel microdialysis experiments, Tempol but not Edaravone reduced extracellular levels of the excitatory neurotransmitter glutamate. Paradoxically, when tested in antioxidant assays in vitro, Edaravone was more effective in scavenging the majority of the ischemia related free radicals and oxidants. The only exception was scavenging of superoxide anion, in which Tempol was superior to Edaravone. Overall, these results suggest that neuroprotective properties of Tempol are determined by its ability to scavenge superoxide and prevent pathological glutamate release.