Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetophenones / administration & dosage
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Acetophenones / pharmacology*
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Animals
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / physiology
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CD11b Antigen / metabolism
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Cerebral Infarction / pathology
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DNA-Binding Proteins
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology*
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Intracranial Hemorrhages / complications
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Intracranial Hemorrhages / drug therapy
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Intracranial Hemorrhages / pathology
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Macrophages / metabolism
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Macrophages / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Microglia / metabolism
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Microglia / pathology
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NADPH Oxidases / antagonists & inhibitors
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Nerve Tissue Proteins / metabolism
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Neuroprotective Agents*
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Nuclear Proteins / metabolism
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Stroke / drug therapy*
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Stroke / etiology
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Stroke / pathology
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Superoxides / metabolism
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Treatment Outcome
Substances
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Acetophenones
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CD11b Antigen
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DNA-Binding Proteins
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Enzyme Inhibitors
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Nerve Tissue Proteins
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NeuN protein, mouse
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Neuroprotective Agents
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Nuclear Proteins
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Platelet Endothelial Cell Adhesion Molecule-1
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Superoxides
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acetovanillone
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NADPH Oxidases