PCSK9 inhibitor improves the neurological function of ischemic stroke via GPNMB/CD44 signaling pathway (PRJCA041706)

Ischemic stroke is the second leading cause of death worldwide, and neuroinflammation has been considered as a key factor in its progression. As a new antilipemic drug, proprotein convertase subtilisin-kexin type 9 inhibitor (PCSK9i) has been demonstrated regulation of inflammatory response. However, whether PCSK9i has an effect on ischemic stroke is unknown. In this study, a transient middle cerebral artery occlusion (tMCAO) model was established to investigate the effect of PCSK9i on neurological function in mice with acute ischemic cerebral infarction. We found that PCSK9i intervention significantly improved neurological function and reduced infarct volume in tMCAO mice. Mechanistically, PCSK9i significantly altered the transcription levels of inflammation-related genes in the peri-infarct cerebral cortex of mice and activated the GPNMB/CD44 signaling pathway. Activated GPNMB/CD44 signaling pathway can negatively regulate the expression levels of pro-inflammatory factors (such as IL-6, iNOS), reduce neuronal death, control excessive inflammation levels and promote functional repair.