AUTHOR=Li Qiang , Zhao Hengli , Pan Pengyu , Ru Xufang , Zuo Shilun , Qu Jie , Liao Bin , Chen Yujie , Ruan Huaizhen , Feng Hua TITLE=Nexilin Regulates Oligodendrocyte Progenitor Cell Migration and Remyelination and Is Negatively Regulated by Protease-Activated Receptor 1/Ras-Proximate-1 Signaling Following Subarachnoid Hemorrhage JOURNAL=Frontiers in Neurology VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2018.00282 DOI=10.3389/fneur.2018.00282 ISSN=1664-2295 ABSTRACT=

Progressive white matter (WM) impairments caused by subarachnoid hemorrhage (SAH) contribute to cognitive deficits and poor clinical prognoses; however, their pathogenetic mechanisms are poorly understood. We investigated the role of nexilin and oligodendrocyte progenitor cell (OPC)-mediated repair in a mouse model of experimental SAH generated via left endovascular perforation. Nexilin expression was enhanced by the elevated migration of OPCs after SAH. Knocking down nexilin by siRNA reduced OPC migration both in vitro and in vivo and abridged WM repair. In contrast, the protease-activated receptor 1 (PAR1), Ras-proximate-1 (RAP1) and phosphorylated RAP1 (pRAP1) levels in WM were elevated after SAH. The genetic inhibition of PAR1 reduced RAP1 and pRAP1 expression, further enhancing nexilin expression. When delivered at an early stage at a concentration of 25 µg/kg, thrombin receptor antagonist peptide along with PAR1 knockdown rescued the down-regulation of myelin basic protein and improved remyelination at the later stage of SAH. Our results suggest that nexilin is required for OPC migration and remyelination following SAH, as it negatively regulates PAR1/RAP1 signaling, thus providing a promising therapeutic target in WM repair and functional recovery.