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Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome-Associated Membrane
Keren Zhou1, Budbazar Enkhjargal1, Zhiyi Xie1
1From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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 CaMKIIα (calcium/calmodulin-dependent protein kinase II α) 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 CaMKIIα and NLRP3 inflammasome, thereby alleviating neurological deficits after SAH. Lysosome-associated membrane protein-1 small interfering RNA abolished the neuroprotective effects of DHLA and increased the level of phosphorylated CaMKIIα, p-TAK1 (phosphorylated transforming growth factor-β-activated kinase), p-JNK (phosphorylated c-Jun-N-terminal kinase), and NLRP3 inflammasome. CaMKIIα 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.
