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Dendrobium Alkaloids Promote Neural Function After Cerebral Ischemia-Reperfusion Injury Through Inhibiting Pyroptosis Induced Neuronal Death in both In Vivo and In Vitro Models.
Neurochemical Research ( IF 4.4 ) Pub Date : 2019-12-21 , DOI: 10.1007/s11064-019-02935-w
Daohang Liu 1 , Zhi Dong 1 , Fei Xiang 1 , Hailin Liu 1 , Yuchun Wang 1 , Qian Wang 1 , Jiangyan Rao 1
Affiliation  

Pyroptosis is a newly identified lytic form of programmed cell death which is characterized by plasma membrane blebbing and rupture. Pyroptosis occurs in cerebral ischemia injury, and contributes to the activation and secretion of the inflammatory cytokines interleukin (IL)-1β, IL-18, and IL-6. Previous reports have found that Dendrobium alkaloids (DNLA) can exert neuroprotective effects against oxygen-glucose deprivation/reperfusion (OGD/R) damage in vitro, but the mechanisms underlying these effects remain elusive. In this study, we investigated whether DNLA exerted therapeutic benefits against cerebral ischemia-reperfusion (CIR) damage via ameliorating pyroptosis and inflammation. OGD/R damage was induced in HT22 cells pretreated with DNLA (0.03, 0.3, or 3 mg/ml, 24 h prior to OGD/R), MCC950 (10 ng/ml, 1 h prior), and VX765 (10 ng/ml, 1 h prior). Neuronal apoptosis, necrosis, pyroptosis, and pathological changes were analyzed 24 h following OGD/R. Further to this, male C57/BL mice pretreated with different concentrations of DNLA (0.5 or 5 mg/kg, ip.) for 24 h and VX765 (50 mg/kg, ip., 1 h before CIR) underwent transient middle cerebral artery occlusion and reperfusion. We found that DNLA pretreatment resulted in a lower neurologic deficit score, a reduced infarct volume, fewer pyroptotic cells, and reduced levels of inflammatory factors 24 h after CIR. Furthermore, DNLA administration also reduced the levels of the pyroptosis-associated proteins Caspase-1 and gasdermin-D, particularly in the hippocampal CA1 region. Similar decreases were observed in the levels of the inflammatory factors IL-1β, IL-6, and IL-18. OGD/R-associated ultrastructural damage was seen to improve following DNLA administration, likely due to the regulation of the tight junction protein Pannexin-1 by DNLA. Overall, these findings demonstrate that DNLA can protect against CIR damage through inhibiting pyroptosis-induced neuronal death, providing new therapeutic insights for CIR injury.

中文翻译:

石斛生物碱在体内和体外模型中通过抑制焦亡诱导的神经元死亡来促进脑缺血再灌注损伤后的神经功能。

焦亡是一种新发现的程序性细胞死亡的溶解形式,其特征是质膜起泡和破裂。焦亡发生在脑缺血损伤中,并有助于炎症细胞因子白细胞介素 (IL)-1β、IL-18 和 IL-6 的激活和分泌。以前的报道发现石斛生物碱(DNLA)可以在体外对氧-葡萄糖剥夺/再灌注(OGD/R)损伤发挥神经保护作用,但这些作用背后的机制仍然难以捉摸。在这项研究中,我们研究了 DNLA 是否通过改善细胞焦亡和炎症对脑缺血再灌注 (CIR) 损伤发挥治疗作用。在用 DNLA(0.03、0.3 或 3 mg/ml,OGD/R 前 24 小时)、MCC950(10 ng/ml,1 小时前)和 VX765(10 ng/毫升,1 小时前)。在 OGD/R 后 24 小时分析神经元凋亡、坏死、细胞焦亡和病理变化。此外,雄性 C57/BL 小鼠用不同浓度的 DNLA(0.5 或 5 mg/kg,ip.)预处理 24 小时,VX765(50mg/kg,ip.,CIR 前 1 小时)经历短暂的大脑中动脉闭塞和再灌注。我们发现 DNLA 预处理导致 CI​​R 后 24 小时神经功能缺损评分降低、梗死体积减少、焦亡细胞减少和炎症因子水平降低。此外,DNLA 给药还降低了细胞焦亡相关蛋白 Caspase-1 和 gasdermin-D 的水平,尤其是在海马 CA1 区域。在炎症因子 IL-1β、IL-6 和 IL-18 的水平中观察到类似的下降。OGD/R 相关的超微结构损伤在 DNLA 给药后得到改善,这可能是由于 DNLA 对紧密连接蛋白 Pannexin-1 的调节。总体而言,这些发现表明 DNLA 可以通过抑制细胞焦亡诱导的神经元死亡来防止 CIR 损伤,为 CIR 损伤提供新的治疗见解。
更新日期:2019-12-21
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