The neuroprotective properties of the superoxide dismutase mimetic tempol correlate with its ability to reduce pathological glutamate release in a rodent model of stroke

• Published in: Free radical biology & medicine 2014-12, Vol.77, p.168-182
• Main Authors: Dohare, Preeti, Hyzinski-García, María C., Vipani, Aarshi, Bowens, Nicole H., Nalwalk, Julia W., Feustel, Paul J., Keller Jr, Richard W., Jourd’heuil, David, Mongin, Alexander A.
• Format: Article
• Language: English
• Subjects: Alanine - metabolism; Animals; Antioxidants; Antipyrine - analogs & derivatives; Antipyrine - chemistry; Antipyrine - pharmacology; Astrocytes - metabolism; Brain - drug effects; Brain - pathology; Cells, Cultured; Cyclic N-Oxides - chemistry; Cyclic N-Oxides - pharmacology; Drug Evaluation, Preclinical; Edaravone; Free Radical Scavengers - chemistry; Free Radical Scavengers - pharmacology; Free radicals; Glutamate release; Glutamic Acid - metabolism; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Male; Molecular Mimicry; Neuroprotection; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Oxidative Stress; Rats, Sprague-Dawley; Spin Labels; Stroke; Superoxide anion; Superoxides - metabolism; Synaptosomes - drug effects; Taurine - metabolism
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2014.08.029

The contribution of oxidative stress to ischemic brain damage is well established. Nevertheless, for unknown reasons, several clinically tested antioxidant therapies have failed to show benefits in human stroke. Based on our previous in vitro work, we hypothesized that the neuroprotective potency of antioxidants is related to their ability to limit the release of the excitotoxic amino acids glutamate and aspartate. We explored the effects of two antioxidants, tempol and edaravone, on amino acid release in the brain cortex, in a rat model of transient occlusion of the middle cerebral artery (MCAo). Amino acid levels were quantified using a microdialysis approach, with the probe positioned in the ischemic penumbra as verified by a laser Doppler technique. Two-hour MCAo triggered a dramatic increase in the levels of glutamate, aspartate, taurine, and alanine. Microdialysate delivery of 10mM tempol reduced the amino acid release by 60–80%, whereas matching levels of edaravone had no effect. In line with these data, an intracerebroventricular injection of tempol but not edaravone (500nmol each, 15min before MCAo) reduced infarction volumes by ~50% and improved neurobehavioral outcomes. In vitro assays showed that tempol was superior at removing superoxide anion, whereas edaravone was more potent at scavenging hydrogen peroxide, hydroxyl radical, and peroxynitrite. Overall, our data suggest that the neuroprotective properties of tempol are probably related to its ability to reduce tissue levels of the superoxide anion and pathological glutamate release and, in such a way, limit progression of brain infarction within ischemic penumbra. These new findings may be instrumental in developing new antioxidant therapies for treatment of stroke. [Display omitted] •Oxidative stress is an important contributor to brain damage in stroke.•Despite preclinical data, several tested antioxidant agents failed in human stroke trials.•We explored a new link between oxidative stress and release of the toxic neurotransmitter glutamate.•The SOD mimetic tempol reduced glutamate release and brain damage in animal stroke.•Our findings may help in developing new, more effective antioxidant therapies.