title: The neuroprotective properties of the superoxide dismutase mimetic tempol correlate with its ability to reduce pathological glutamate release in a rodent model of stroke.
abstract: 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 (500 nmol each, 15 min 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.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Dohare
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: María C
authors.initials: MC
authors.lastname: Hyzinski-García
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Aarshi
authors.initials: A
authors.lastname: Vipani
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Bowens
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Julia W
authors.initials: JW
authors.lastname: Nalwalk
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Feustel
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Keller
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jourd'heuil
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA. Electronic address: mongina@mail.amc.edu.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Mongin
mesh_terms: D000409:Alanine / Q000378:metabolism; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018716:Molecular Mimicry; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects; D013654:Taurine / Q000378:metabolism
chemical_list: D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D013113:Spin Labels; D013481:Superoxides; D013654:Taurine; D018698:Glutamic Acid; D000409:Alanine; D000077553:Edaravone; D000983:Antipyrine; C001803:tempol
keywords: Antioxidants; Free radicals; Glutamate release; Neuroprotection; Oxidative stress; Stroke; Superoxide anion