Abstract
The neuroprotective effects of minocycline-which is broadly protective in neurologic-disease models featuring cell death and is being evaluated in clinical trials-were investigated both in vitro and in vivo. For the in vivo study, focal cerebral ischemia was induced by permanent middle cerebral artery occlusion in mice. Minocycline at 90 mg/kg intraperitoneally administered 60 min before or 30 min after (but not 4 h after) the occlusion reduced infarction, brain swelling, and neurologic deficits at 24 h after the occlusion. For the in vitro studies, we used cortical-neuron cultures from rat fetuses in which neurotoxicity was induced by 24-h exposure to 500 microM glutamate. Furthermore, the effects of minocycline on oxidative stress [such as lipid peroxidation in mouse forebrain homogenates and free radical-scavenging activity against diphenyl-p-picrylhydrazyl (DPPH)] were evaluated to clarify the underlying mechanism. Minocycline significantly inhibited glutamate-induced cell death at 2 microM and lipid peroxidation and free radical scavenging at 0.2 and 2 microM, respectively. These findings indicate that minocycline has neuroprotective effects in vivo against permanent focal cerebral ischemia and in vitro against glutamate-induced cell death and that an inhibition of oxidative stress by minocycline may be partly responsible for these effects.
MeSH terms
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Animals
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Antioxidants / pharmacology
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Benzimidazoles / metabolism
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Benzoxazoles
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Biphenyl Compounds / metabolism
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Brain Edema / etiology
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Brain Edema / prevention & control
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Brain Infarction / etiology
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Brain Infarction / prevention & control
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Cell Death / drug effects
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Cell Survival / drug effects
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Cells, Cultured
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Cerebral Cortex / cytology
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Chromans / pharmacology
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Dose-Response Relationship, Drug
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Drug Interactions
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Embryo, Mammalian
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Fluorescent Dyes / metabolism
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Glutamic Acid / pharmacology
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Hydrazines / metabolism
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Infarction, Middle Cerebral Artery / complications
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Infarction, Middle Cerebral Artery / drug therapy
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Inhibitory Concentration 50
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Ischemia / etiology
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Ischemia / pathology
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Ischemia / prevention & control*
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Lipid Peroxidation / drug effects
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Male
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Mice
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Minocycline / therapeutic use*
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Neurons / drug effects*
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Neuroprotective Agents / therapeutic use*
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Oxidative Stress / drug effects*
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Oxidative Stress / physiology
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Picrates
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Quinolinium Compounds
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Saponins / pharmacology
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Tetrazolium Salts
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Time Factors
Substances
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Antioxidants
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Benzimidazoles
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Benzoxazoles
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Biphenyl Compounds
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Chromans
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Fluorescent Dyes
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Hydrazines
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MK 800-62F1
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Neuroprotective Agents
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Picrates
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Quinolinium Compounds
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Saponins
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Tetrazolium Salts
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YO-PRO 1
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Glutamic Acid
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triphenyltetrazolium
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1,1-diphenyl-2-picrylhydrazyl
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Minocycline
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bisbenzimide ethoxide trihydrochloride
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6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid