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

作者：Zhou, Keren; Enkhjargal, Budbazar; Xie, Zhiyi; Sun, Chengmei; Wu, Lingyun; Malaguit, Jay; Chen, Sheng; Tang, Jiping; Zhang, Jianmin^*; Zhang, John H.

来源：Stroke, 2018, 49(1): 175-+.

DOI：10.1161/STROKEAHA.117.018593

• calcium-calmodulin-dependent protein kinase type 2
• dihydrolipoic acid
• inflammasomes
• lysosomal-associated membrane protein 1
• subarachnoid hemorrhage

Background and Purpose-The NLRP3 (nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a crucial component of the inflammatory response in early brain injury 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. @@@ Methods-SAH was induced by endovascular perforation in male Sprague-Dawley rats. DHLA was administered intraperitoneally 1 hour after SAH. Small interfering RNA for lysosome-associated membrane protein-1 and CaMKII alpha (calcium/calmodulin-dependent protein kinase II alpha) was administered through intracerebroventricular 48 hours before SAH induction. SAH grade evaluation, short-and long-term neurological function testing, Western blot, and immunofluorescence staining experiments were performed. @@@ Results-DHLA treatment increased the expression of lysosome-associated membrane protein-1 and decreased phosphorylated CaMKIIa and NLRP3 inflammasome, thereby alleviating neurological deficits after SAH. Lysosomeassociated membrane protein-1 small interfering RNA abolished the neuroprotective effects of DHLA and increased the level of phosphorylated CaMKIIa, p-TAK1 (phosphorylated transforming growth factor-beta-activated kinase), p-JNK (phosphorylated c-Jun-N-terminal kinase), and NLRP3 inflammasome. CaMKIIa small interfering RNA downregulated the expression of p-TAK1, p-JNK, and NLRP3 and improved the neurobehavior after SAH. @@@ Conclusions-DHLA treatment improved neurofunction and alleviated inflammation through the lysosome-associated membrane protein-1/CaMKII/TAK1 pathway in early brain injury after SAH. DHLA may provide a promising treatment to alleviate early brain injury after SAH. @@@ Visual Overview-An online visual overview is available for this article.

• 出版日期2018-1
• 单位浙江大学