A type-II positive allosteric modulator of α7 nAChRs reduces brain injury and improves neurological function after focal cerebral ischemia in rats.
A type-II positive allosteric modulator of α7 nAChRs reduces brain injury and improves neurological function after focal cerebral ischemia in rats.
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DOI：
10.1371/journal.pone.0073581
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Uteshev VV
中科院分区：
文献类型：
--
作者：
Sun F;Jin K;Uteshev VV
在缺乏临床有效的缺血性卒中治疗方法的情况下，迫切需要开发新的治疗概念和方法来预防继发于脑缺血的脑损伤。本研究检验了以下假设：在缺血性卒中动物模型中，在局灶性脑缺血发作后6小时给予PNU-120596（α7烟碱乙酰胆碱受体（nAChR）的II型正变构调节剂（PAM-II））可显著降低脑损伤和神经功能缺损。通过短暂（90分钟）大脑中动脉闭塞（MCAO）诱导局灶性脑缺血。然后将动物分成两组，并静脉内（i. v.）MCAO后6小时，给予1 mg/kg PNU-120596（给药组）或仅给予溶媒（未给药组）。在MCAO后24小时进行脑梗死体积测量和神经行为测试。PNU-120596显著减少脑梗死体积并改善神经功能，如Bederson、滚柱和阶梯行走试验结果所证明。这些结果预示PAMs-II作为内源性α7 nAChR依赖性胆碱能通路的有效募集剂和激活剂具有很高的治疗潜力，可减少脑缺血性卒中后的脑损伤并改善神经功能。
In the absence of clinically-efficacious therapies for ischemic stroke there is a critical need for development of new therapeutic concepts and approaches for prevention of brain injury secondary to cerebral ischemia. This study tests the hypothesis that administration of PNU-120596, a type-II positive allosteric modulator (PAM-II) of α7 nicotinic acetylcholine receptors (nAChRs), as long as 6 hours after the onset of focal cerebral ischemia significantly reduces brain injury and neurological deficits in an animal model of ischemic stroke. Focal cerebral ischemia was induced by a transient (90 min) middle cerebral artery occlusion (MCAO). Animals were then subdivided into two groups and injected intravenously (i.v.) 6 hours post-MCAO with either 1 mg/kg PNU-120596 (treated group) or vehicle only (untreated group). Measurements of cerebral infarct volumes and neurological behavioral tests were performed 24 hrs post-MCAO. PNU-120596 significantly reduced cerebral infarct volume and improved neurological function as evidenced by the results of Bederson, rolling cylinder and ladder rung walking tests. These results forecast a high therapeutic potential for PAMs-II as effective recruiters and activators of endogenous α7 nAChR-dependent cholinergic pathways to reduce brain injury and improve neurological function after cerebral ischemic stroke.
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影响因子：
4.7
作者：
Callahan PM;Hutchings EJ;Kille NJ;Chapman JM;Terry AV Jr
通讯作者：
Terry AV Jr
影响因子：
5.3
作者：
Bitner, Robert S.;Bunnelle, William H.;Gopalakrishnan, Murali
通讯作者：
Gopalakrishnan, Murali
影响因子：
3.1
作者：
Akaike, Akinori;Takada-Takatori, Yuki;Izumi, Yasuhiko
通讯作者：
Izumi, Yasuhiko
影响因子：
8.3
作者：
BEDERSON, JB;PITTS, LH;BARTKOWSKI, H
通讯作者：
BARTKOWSKI, H
影响因子：
3.3
作者：
Egea, J.;Rosa, A. O.;Garcia, A. G.
通讯作者：
Garcia, A. G.