Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage.
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.
Morimoto
Nobutaka
N
Department of Biofunctional Molecules, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.
Shimazawa
Masamitsu
M
Yamashima
Tetsumori
T
Nagai
Hiroichi
H
Hara
Hideaki
H
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001562:Benzimidazoles / Q000378:metabolism; D001583:Benzoxazoles; D001713:Biphenyl Compounds / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005456:Fluorescent Dyes / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D006834:Hydrazines / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D007511:Ischemia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008911:Minocycline / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010851:Picrates; D011806:Quinolinium Compounds; D012503:Saponins / Q000494:pharmacology; D013778:Tetrazolium Salts; D013997:Time Factors
D000975:Antioxidants; D001562:Benzimidazoles; D001583:Benzoxazoles; D001713:Biphenyl Compounds; D002839:Chromans; D005456:Fluorescent Dyes; D006834:Hydrazines; C413564:MK 800-62F1; D018696:Neuroprotective Agents; D010851:Picrates; D011806:Quinolinium Compounds; D012503:Saponins; D013778:Tetrazolium Salts; C089813:YO-PRO 1; D018698:Glutamic Acid; C009591:triphenyltetrazolium; C004931:1,1-diphenyl-2-picrylhydrazyl; D008911:Minocycline; C017807:bisbenzimide ethoxide trihydrochloride; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid