Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke.
Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke.
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吩噻嗪通过 PI3K/Akt 调节增强实验性卒中中轻度低温诱导的神经保护
DOI：
10.1038/s41598-017-06752-5
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发表时间：
2017-08-07
影响因子：
4.6
通讯作者：
Ding Y
中科院分区：
文献类型：
--
作者：
An H;Duan Y;Wu D;Yip J;Elmadhoun O;Wright JC;Shi W;Liu K;He X;Shi J;Jiang F;Ji X;Ding Y
物理低温治疗一直被认为是一种很有前途的缺血性脑卒中神经保护治疗方法，但治疗的各种并发症以及治疗时间和深度不切实际，大大缩小了其临床应用范围。本研究采用可逆性右大脑中动脉闭塞（MCAO） 2 h模型。我们将低温治疗（33-35°C持续1小时）与吩噻嗪类神经抑制剂（氯丙嗪和异丙嗪）联合使用作为神经保护剂，目的是在仅使用温和温度的情况下增强其疗效。我们还研究了其对磷脂酰肌醇3激酶/蛋白激酶B （PI3K/Akt）凋亡通路的治疗作用。联合治疗使缺血大鼠直肠、皮层和纹状体温度的降低明显快于单纯低温治疗（P < 0.01），脑梗死体积和神经功能缺损的减少更明显（P < 0.01）。联合治疗显著提高了P - akt和抗凋亡蛋白（Bcl-2和Bcl-xL）的表达（P < 0.05），降低了促凋亡蛋白（AIF和Bax）的表达（P < 0.05）。最后，治疗的神经保护作用被p-Akt抑制剂阻断。通过低温联合吩噻嗪，我们显著增强了亚低温的神经保护作用。该研究还揭示了这些作用可能涉及PI3K/Akt信号通路和凋亡途径的分子机制。
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.
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影响因子：
2.9
作者：
Dwyer, DS;Lu, XH;Bradley, RJ
通讯作者：
Bradley, RJ
影响因子：
8.3
作者：
DeGraba, TJ;Hallenbeck, JM;Kelly, BJ
通讯作者：
Kelly, BJ
影响因子：
2.9
作者：
Fu, Paul;Peng, Changya;Ding, Yuchuan
通讯作者：
Ding, Yuchuan
氯丙嗪和异丙嗪对严重短暂性和永久性缺血性中风的神经保护作用。
影响因子：
5.1
作者：
Geng, Xiaokun;Li, Fengwu;Ding, Yuchuan
通讯作者：
Ding, Yuchuan
DOI：
10.1093/jnen/62.4.329
发表时间：
2003-04-01
影响因子：
3.2
作者：
Ferrer, I;Planas, AM
通讯作者：
Planas, AM