Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke

Abstract Physical hypothermia has long been considered a promising neuroprotective treatment of ischemic stroke, but the treatment’s various complications along with the impractical duration and depth of therapy significantly narrow its clinical scope. In the present study, the model of reversible r...

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Autores principales:	Hong An, Yunxia Duan, Di Wu, James Yip, Omar Elmadhoun, Joshua C. Wright, Wenjuan Shi, Kaiyin Liu, Xiaoduo He, Jingfei Shi, Fang Jiang, Xunming Ji, Yuchuan Ding
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/43ed0bf086ca49439ce752cf2b58ae76
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spelling	oai:doaj.org-article:43ed0bf086ca49439ce752cf2b58ae762021-12-02T16:08:22ZPhenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke10.1038/s41598-017-06752-52045-2322https://doaj.org/article/43ed0bf086ca49439ce752cf2b58ae762017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06752-5https://doaj.org/toc/2045-2322Abstract Physical hypothermia has long been considered a promising neuroprotective treatment of ischemic stroke, but the treatment’s various complications along with the impractical duration and depth of therapy significantly narrow its clinical scope. In the present study, the model of reversible right middle cerebral artery occlusion (MCAO) for 2 h was used. We combined hypothermia (33–35 °C for 1 h) with phenothiazine neuroleptics (chlorpromazine & promethazine) as additive neuroprotectants, with the aim of augmenting its efficacy while only using mild temperatures. We also investigated its therapeutic effects on the Phosphatidylinositol 3 kinase/Protein kinase B (PI3K/Akt) apoptotic pathway. The combination treatment achieved reduction in ischemic rat temperatures in the rectum, cortex and striatum significantly (P < 0.01) faster than hypothermia alone, accompanied by more obvious (P < 0.01) reduction of brain infarct volume and neurological deficits. The combination treatment remarkably (P < 0.05) increased expression of p-Akt and anti-apoptotic proteins (Bcl-2 and Bcl-xL), while reduced expression of pro-apoptotic proteins (AIF and Bax). Finally, the treatment’s neuroprotective effects were blocked by a p-Akt inhibitor. By combining hypothermia with phenothiazines, we significantly enhanced the neuroprotective effects of mild hypothermia. This study also sheds light on the possible molecular mechanism for these effects which involves the PI3K/Akt signaling and apoptotic pathway.Hong AnYunxia DuanDi WuJames YipOmar ElmadhounJoshua C. WrightWenjuan ShiKaiyin LiuXiaoduo HeJingfei ShiFang JiangXunming JiYuchuan DingNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hong An Yunxia Duan Di Wu James Yip Omar Elmadhoun Joshua C. Wright Wenjuan Shi Kaiyin Liu Xiaoduo He Jingfei Shi Fang Jiang Xunming Ji Yuchuan Ding Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke
description	Abstract Physical hypothermia has long been considered a promising neuroprotective treatment of ischemic stroke, but the treatment’s various complications along with the impractical duration and depth of therapy significantly narrow its clinical scope. In the present study, the model of reversible right middle cerebral artery occlusion (MCAO) for 2 h was used. We combined hypothermia (33–35 °C for 1 h) with phenothiazine neuroleptics (chlorpromazine & promethazine) as additive neuroprotectants, with the aim of augmenting its efficacy while only using mild temperatures. We also investigated its therapeutic effects on the Phosphatidylinositol 3 kinase/Protein kinase B (PI3K/Akt) apoptotic pathway. The combination treatment achieved reduction in ischemic rat temperatures in the rectum, cortex and striatum significantly (P < 0.01) faster than hypothermia alone, accompanied by more obvious (P < 0.01) reduction of brain infarct volume and neurological deficits. The combination treatment remarkably (P < 0.05) increased expression of p-Akt and anti-apoptotic proteins (Bcl-2 and Bcl-xL), while reduced expression of pro-apoptotic proteins (AIF and Bax). Finally, the treatment’s neuroprotective effects were blocked by a p-Akt inhibitor. By combining hypothermia with phenothiazines, we significantly enhanced the neuroprotective effects of mild hypothermia. This study also sheds light on the possible molecular mechanism for these effects which involves the PI3K/Akt signaling and apoptotic pathway.
format	article
author	Hong An Yunxia Duan Di Wu James Yip Omar Elmadhoun Joshua C. Wright Wenjuan Shi Kaiyin Liu Xiaoduo He Jingfei Shi Fang Jiang Xunming Ji Yuchuan Ding
author_facet	Hong An Yunxia Duan Di Wu James Yip Omar Elmadhoun Joshua C. Wright Wenjuan Shi Kaiyin Liu Xiaoduo He Jingfei Shi Fang Jiang Xunming Ji Yuchuan Ding
author_sort	Hong An
title	Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke
title_short	Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke
title_full	Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke
title_fullStr	Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke
title_full_unstemmed	Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke
title_sort	phenothiazines enhance mild hypothermia-induced neuroprotection via pi3k/akt regulation in experimental stroke
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/43ed0bf086ca49439ce752cf2b58ae76
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Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke

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