T0901317, a liver X receptor agonist, ameliorates perinatal white matter injury induced by ischemia and hypoxia in neonatal rats

作者：Ting Gao, Tianyang Qian, Tianwei Wang, Yu Su, Han Qiu, Wan Tang, Qinghe Xing, Laishuan Wang · 发表于：Neuroscience Letters · 年份：2022 · DOI：10.1016/j.neulet.2022.136994 · 被引用次数：17 · 研究领域：Neonatal and fetal brain pathology、Fatty Acid Research and Health、Neuroscience and Neuropharmacology Research

Perinatal white matter injury (PWMI) can lead to permanent neurological damage in preterm infants and bring a huge economic burden to their families and society. Liver X receptors (LXRs) are transcription factors that have been confirmed to mediate the myelination process under physiological conditions and are involved in regulating neurogenesis in adult animal models of acute and chronic cerebral ischemia. However, the role of LXRs in PWMI induced by both ischemic and hypoxic stimulation in the immature brain has not been reported. Herein, we investigated the role of LXRs in a neonatal rat model of white matter loss after hypoxia-ischemia (HI) injury through intraperitoneal injection of the LXR agonist T0901317 (T09) 1 day before and 15 min postinjury. The in vivo data showed that T09 treatment significantly facilitated myelination and ameliorated neurological behavior after PWMI. Moreover, T09 enhanced the proliferation of oligodendrocyte lineage cells and reduced microgliosis and astrogliosis in the microenvironment for oligodendrocytes (OLs), maintaining a healthy microenvironment for myelinating OLs. In vitro data suggested that the expression of the myelin-related genes Plp and Cnpase was increased in OLN-93 cells after T09 intervention compared with OLN-93 cells injured by oxygen and glucose deprivation (OGD). In primary mixed astrocytes/microglia cells, T09 also reduced the expression of Il6, Cox2, Tnfa and Il10 that was induced by OGD. Mechanistically, the mRNA expre...