Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome-Associated Membrane Protein-1/Calcium/Calmodulin-Dependent Protein Kinase II/TAK1 Pathways After Subarachnoid Hemorrhage in Rat.
Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome-Associated Membrane Protein-1/Calcium/Calmodulin-Dependent Protein Kinase II/TAK1 Pathways After Subarachnoid Hemorrhage in Rat.
复制标题
二氢硫辛酸通过大鼠蛛网膜下腔出血后溶酶体相关膜蛋白-1/钙/钙调蛋白依赖性蛋白激酶 II/TAK1 通路抑制溶酶体破裂和 NLRP3
DOI：
10.1161/strokeaha.117.018593
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发表时间：
2018-01
期刊：
影响因子：
8.3
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Zhou K;Enkhjargal B;Xie Z;Sun C;Wu L;Malaguit J;Chen S;Tang J;Zhang J;Zhang JH
NLRP 3炎性小体是蛛网膜下腔出血（SAH）后早期脑损伤（EBI）中炎症反应的重要组成部分。在这项研究中，我们研究了二氢硫辛酸（DHLA）在溶酶体破裂，NLRP 3激活中的作用，并确定了潜在的途径。在雄性Sprague-Dawley大鼠中通过血管内穿孔诱导SAH。SAH后1h腹腔注射DHLA。在SAH诱导前48 h通过侧脑室（i.c. v）注射针对溶酶体相关膜蛋白1（LAMP1）和钙/钙调素依赖性蛋白激酶II α（CaMKII α）的小干扰核糖核酸（siRNA）。进行SAH分级、神经功能短期和长期检测、免疫印迹和免疫荧光染色实验。DHLA治疗增加了LAMP 1的表达，减少了磷酸化CaMKII α（p-CaMKII α）和NLRP 3炎性体，从而减轻了SAH后的神经功能缺损。LAMP1 siRNA可阻断DHLA的神经保护作用，增加p-CaMK Ⅱ α、p-TAK 1、p-JNK和NLRP 3炎性小体的表达。CaMKII α siRNA下调SAH后p-TAK1、p-JNK和NLRP3的表达，改善SAH后神经行为。DHLA治疗通过LAMP1/CaMKII/TAK1通路改善SAH后EBI的神经功能并减轻炎症。DHLA可能为缓解SAH后EBI提供一种有希望的治疗方法。
The NLRP3 inflammasome is a crucial component of the inflammatory response in early brain injury (EBI) after subarachnoid hemorrhage (SAH). In this study we investigated a role of dihydrolipoic acid (DHLA) in lysosomal rupture, NLRP3 activation, and determined the underlying pathway. SAH was induced by endovascular perforation in male Sprague-Dawley rats. DHLA was administered intraperitoneally 1 hour (h) after SAH. Small interfering ribonucleic acid (siRNA) for lysosome-associated membrane protein-1 (LAMP1) and calcium/calmodulin-dependent protein kinase II α (CaMKIIα) were administered through intracerebroventricular (i.c.v) 48 h before SAH induction. SAH grade evaluation, short and long-term neurological function testing, Western blot and immunofluorescence staining experiments were performed. DHLA treatment increased the expression of LAMP1 and decreased phosphorylated CaMKIIα (p-CaMKIIα) and NLRP3 inflammasome, thereby alleviating neurological deficits following SAH. LAMP1 siRNA abolished the neuroprotective effects of DHLA and increased the level of p-CaMKIIα, p-TAK1, p-JNK and NLRP3 inflammasome. CaMKIIα siRNA downregulated the expression of p-TAK1, p-JNK and NLRP3 and improved the neurobehavior after SAH. DHLA treatment improved neurofunction and alleviated inflammation through the LAMP1/CaMKII/TAK1 pathway in EBI after SAH. DHLA may provide a promising treatment to alleviate EBI after SAH.