title: w007B protects brain against ischemia-reperfusion injury in rats through inhibiting inflammation, apoptosis and autophagy.
abstract: This study was designed to investigate the effect of w007B, a newly synthesized derivative of honokiol, on MCAO reperfusion, and its therapeutic time window and related mechanisms in rats. Neurological deficit scores, infarct size and brain water content were measured after 24 h reperfusion following 2 h ischemia. The results showed that w007B (10 and 50 μg/kg, IV immediately after reperfusion) markedly decreased neurological deficit scores, reduced infarct size and alleviated brain water content, and then 50 μg/kg w007B given within 3 h after reperfusion (5 h after ischemia) significantly attenuated ischemia-induced brain injury. Additionally, no sign of toxicity was observed when a single dose of 50mg/kg w007B (1000 times of the highest effective dose, IP) was administered. To explore the underlying mechanisms, the expression level of apoptosis, inflammation and autophagy-related markers in brain tissue were detected with kits or by western blot. It was observed that w007B rapidly and significantly reduced caspase-3 activity and NO production in the injured semi-brain, and also lowered the level of the p65 subunit of NF-κB in the nucleus. Besides, it also reduced the expression of Beclin-1 and LC3B-II, and increased the level of p62, the autophagy-related proteins in I/R-injured hemisphere. In conclusion, w007B exerts neuroprotective effect on cerebral ischemia-reperfusion injury with wider therapeutic time window and better safety; its mechanisms may be associated with its anti-inflammation, anti-apoptosis and anti-autophagy action. These results suggest that w007B shows strong potential as a clinical neuroprotective candidate for the treatment of ischemic stroke.
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Qixin
authors.initials: Q
authors.lastname: Bu
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Beijing Honghui New Medical Technology Co. Ltd., Beijing Daxing Biological Medicine Industry Base, Beijing 102600, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: wangyinye@bjmu.edu.cn.
authors.forename: Yinye
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology*; D017705:Lignans / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D012737:Sex Factors; D013997:Time Factors; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001713:Biphenyl Compounds; D017705:Lignans; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009569:Nitric Oxide; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: Apoptosis; Autophagy; Cerebral ischemia–reperfusion; Inflammation; Therapeutic time window; w007B