Knockdown of G protein-coupled receptor-17 (GPR17) facilitates the regeneration and repair of myelin sheath post-periventricular leukomalacia (PVL)

Abstract

ABSTRACT The G protein-coupled receptor-17 (GPR17) plays an important role in regulating the differentiation of oligodendrocytes and remyelination, which is a key negative regulator of oligodendrocyte differentiation. The present study aimed to investigate the function of GPR17 in the white matter of periventricular leukomalacia (PVL) neonatal rats. The PVL model was established in 2-day old neonatal rats by intracerebral injection of LPS (1 mg/kg). Compared to sham, GPR17 was significantly upregulated, while Olig1 was significantly downregulated in the PVL group at 1 d, 3 days, and 7 days post-modeling. Compared to the negative control (NC) group, the expression of GPR17 was suppressed, while that of Olig1 was elevated in the siRNA-GPR17 group as time progressed; the opposite results were observed in the GPR17-overexpressed group. Decreased formation of myelin sheaths as well as poor structure and loose arrangement were observed in the PVL group. Similar observations were found in the PVL + siRNA-GPR17 group at 1 d and 3 days post-modeling. However, on day 7 post-modeling, a dramatic increase in the formation of myelin sheath as well as thicker myelin sheaths were observed in the PVL + siRNA-GPR17 group. The migration ability of oligodendrocyte progenitor cells (OPCs) isolated from animals was found to be significantly suppressed in the GPR17-overexpressed group, accompanied by the downregulation of Olig1. Taken together, the regeneration and repair of myelin sheaths post-PVL white matter injury were induced by downregulating the GPR17 gene, which elevated the expression of Olig1.