title: Honokiol protects brain against ischemia-reperfusion injury in rats through disrupting PSD95-nNOS interaction.
abstract: Honokiol, a major bioactive constituent of the bark of Magnolia officinalis has been confirmed to have the neuroprotective effect on ischemic stroke in rats. This study was designed to observe the therapeutic time window of honokiol microemulsion on cerebral ischemia-reperfusion injury to support its potential for future clinical trials and further explore the underlying mechanisms. Honokiol microemulsion (50μg/kg, i.v. at 0, 1 or 3h after reperfusion) significantly reduced neurological deficit, infarct volume and brain water content in rats subjected to cerebral ischemia-reperfusion, and honokiol (0.1-10μM) significantly attenuated oxygen-glucose deprivation- or glutamate-induced injury of fetal rat cortical neurons. In co-immunoprecipitation and western blot test, honokiol decreased the intensity of nNOS related to PSD95 but failed to affect that of PSD95 related to NR2B in NR2B-PSD95-nNOS complex, and it also inhibited the translocation of nNOS from cytosol to membrane without affecting total nNOS expression, and then markedly decreased NO production in cortical neurons. Besides, the results of whole-cell patch-clamp recordings showed that honokiol reversibly inhibited the NMDA current by about 64%. In conclusion, honokiol has a therapeutic window of at least 5h after the onset of cerebral ischemia or 3h after reperfusion in rats, which may be in part ascribed to the disruption of the PSD95-nNOS interaction leading to the inhibition of neurotoxic NO production.
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Hu
authors.forename: Xiling
authors.initials: X
authors.lastname: Bian
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liu
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Zhang
authors.forename: Shizhong
authors.initials: S
authors.lastname: Chen
authors.forename: Kewei
authors.initials: K
authors.lastname: Wang
authors.forename: Yinye
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D006690:Bisbenzimidazole; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D004396:Coloring Agents; D003600:Cytosol / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000633:toxicity; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017705:Lignans / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015427:Reperfusion Injury / Q000188:drug therapy*; D014178:Translocation, Genetic; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001713:Biphenyl Compounds; D006690:Bisbenzimidazole; D002492:Central Nervous System Depressants; D004396:Coloring Agents; D000076122:Disks Large Homolog 4 Protein; D005947:Glucose; D018698:Glutamic Acid; D047908:Intracellular Signaling Peptides and Proteins; D007770:L-Lactate Dehydrogenase; D017705:Lignans; D008565:Membrane Proteins; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D016194:Receptors, N-Methyl-D-Aspartate; C501449:Dlg4 protein, rat; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols