title: Hyperforin attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6 channels degradation.
abstract: Hyperforin, a lipophilic constituent of medicinal herb St John's wort, has been identified as the main active ingredient of St John's wort extract for antidepressant action by experimental and clinical studies. Hyperforin is currently known to activate transient receptor potential canonical (subtype) 6 (TRPC6) channel, increase the phosphorylated CREB (p-CREB), and has N-methyl-D-aspartate receptor-antagonistic effect that convert potential neuroprotective effects in vitro. However, the protective effects of hyperforin on ischemic stroke in vivo remain controversial and its neuroprotective mechanisms are still unclear. This study was designed to examine the effects of intracerebroventricular (i.c.v.) injection of hyperforin on transient focal cerebral ischemia in rats. Hyperforin, when applied immediately after middle cerebral artery occlusion (MCAO) onset, significantly reduced infarct volumes and apoptotic cells, and also increased neurologic scores at 24 hours after reperfusion accompanied by elevated TRPC6 and p-CREB activity and decreased SBDP145 activity. When MEK or CaMKIV activity was specifically inhibited, the neuroprotective effect of hyperforin was attenuated, and we observed a correlated decrease in CREB activity. In conclusion, our results clearly showed that i.c.v. injection of hyperforin immediately after MCAO onset blocked calpain-mediated TRPC6 channels degradation, and then to stimulate the Ras/MEK/ERK and CaMKIV pathways that converge on CREB activation, contributed to neuroprotection.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lin
authors.forename: Jian-Cheng
authors.initials: JC
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Fu
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Zhi-Lin
authors.initials: ZL
authors.lastname: Wu
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000378:metabolism*; D013729:Terpenes / Q000494:pharmacology*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D050052:TRPC Cation Channels; D013729:Terpenes; C492145:Trpc6 protein, rat; D010696:Phloroglucinol; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517686:Camk4 protein, rat; D002154:Calpain; C001654:hyperforin