title: Involvement of arterial baroreflex and nicotinic acetylcholine receptor α7 subunit pathway in the protection of metformin against stroke in stroke-prone spontaneously hypertensive rats.
abstract: Stroke is a leading cause of mortality and disability worldwide. There is growing evidence that metformin (Met) has potent neuroprotective effects; however, its mechanisms remain unclear. We examined the role of the arterial baroreflex and cholinergic-α7 nicotinic acetylcholine receptor (α7nAChR) anti-inflammory pathway in the beneficial effects of Met against stroke. Stroke-prone spontaneously hypertensive rats (SHRSP) were used to observe stroke development indicated by lifespan of SHRSP and the ischemic injury induced by permanent middle cerebral artery occlusion (MCAO). Sinoaortic denervation was used to inactivate the arterial baroreflex. MCAO were also performed in α7nAChR knockout (KO) mice. Briefly, Met increased the life span of SHRSP and reduced the infarct area induced by MCAO. Met also improved the function of arterial baroreflex. The beneficial effects of Met on stroke were markedly attenuated by blunting the arterial baroreflex. Met up-regulated the expression of vesicular acetylcholine transporter (VAChT) and α7nAChR, down-regulated the level of pro-inflammtory cytokines in serum and peri-infarct of ischemic brain. Arterial baroreflex dysfunction decreased the expression of VAchT and α7nAChR, showed upward tendency in the level of pro-inflammtory cytokines. Most importantly, arterial baroreflex dysfunction nearly abolished such effect of Met on cholinergic signaling. In addition, the α7nAChR KO mice also had significantly worse ischemic damage induced by MCAO, and neuroprotection of Met disappeared in α7nAChR KO mice. In conclusion, Met improved the arterial baroreflex function, and then enhancing cholinergic anti-inflammatory pathway in an α7nAChR-dependent manner, thereby effectively prevent ischemic induced brain injury and delayed stroke onset in SHRSP.
authors.affiliation: Department of Pharmacology, Jinan Military General Hospital, Jinan, Shandong, China.
authors.forename: Jin-Min
authors.initials: JM
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Jinan Military General Hospital, Jinan, Shandong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Radiotheropy, The Forth Hospital of Jinan City, Jinan, Shandong, China.
authors.forename: Xue-Cai
authors.initials: XC
authors.lastname: Niu
authors.affiliation: Department of Pharmacology, Jinan Military General Hospital, Jinan, Shandong, China.
authors.forename: He
authors.initials: H
authors.lastname: Shu
authors.affiliation: Department of Orthopaedics, Jinan Military General Hospital, Jinan, Shandong, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Ding-Feng
authors.initials: DF
authors.lastname: Su
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Ai-Jun
authors.initials: AJ
authors.lastname: Liu
authors.affiliation: Division of Pharmacy, Tongji Hospital, Tongji University School of Medicine, 389 Xin Cun Road, Shanghai 200065, China. Electronic address: zdq_0726@163.com.
authors.forename: De-Qiu
authors.initials: DQ
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Jinan Military General Hospital, Jinan, Shandong, China. Electronic address: xjj8605@163.com.
authors.forename: Jian-Jiang
authors.initials: JJ
authors.lastname: Xu
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000503:physiopathology; D017704:Baroreflex / Q000187:drug effects*; D002545:Brain Ischemia / Q000150:complications; D016207:Cytokines / Q000097:blood; D004198:Disease Susceptibility; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000150:complications / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018696:Neuroprotective Agents; C493461:Slc18a3 protein, rat; D050494:Vesicular Acetylcholine Transport Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; D008687:Metformin
keywords: Arterial baroreflex; Metformin; Nicotinic acetylcholine receptor α7 subunit; Stoke; Stroke-prone spontaneously hypertensive rats