Apocynin improves outcome in experimental stroke with a narrow dose range.
Inflammation following ischemic stroke is known to contribute to injury. NADPH oxidase (NOX) is a major enzyme system originally studied in immune cells that leads to superoxide (O.*) generation. Apocynin is a NOX inhibitor that has been studied as a potential treatment in experimental stroke. Here we explored the effect of different doses of apocynin in a mouse model of 2 h transient middle cerebral artery occlusion (tMCAO) followed by 22 h reperfusion. Apocynin, given i.v. at a dose of 2.5 mg/kg 30 min before reperfusion, improved neurological function (P<0.01), reduced infarct volume (P<0.05), and reduced the incidence of cerebral hemorrhage (P<0.05), but not at higher doses of 3.75 and 5 mg/kg, where it actually increased brain hemorrhage. Apocynin also tended to reduce mortality at the lower dose, but not at higher doses. Using hydroethine fluorescence to delineate O.* in the brain, neurons and some microglia/macrophages, but not vascular endothelial cells were found to contain O.*. Apocynin at protective doses markedly prevented ischemia-induced increases in O.*. Our data suggested that apocynin can protect against experimental stroke, but with a narrow therapeutic window.
Department of Neurology, University of California, San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
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D000098:Acetophenones / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D039481:CD11b Antigen / Q000378:metabolism; D002544:Cerebral Infarction / Q000473:pathology; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D020300:Intracranial Hemorrhages / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents; D009687:Nuclear Proteins / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D013481:Superoxides / Q000378:metabolism; D016896:Treatment Outcome
D000098:Acetophenones; D039481:CD11b Antigen; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013481:Superoxides; C056165:acetovanillone; D019255:NADPH Oxidases