Microglial Inhibition Promotes Proliferation and Differentiation of Neural Stem Cells via <scp>STAT3</scp> / <scp>SDF</scp> ‐1/ <scp>CXCR4</scp> Signaling Pathway in Hypoxic–Ischemic Encephalopathy

Neonatal hypoxic-ischemic encephalopathy (HIE) may induce substantial neuronal damage. In particular, an overactivation of microglia following HIE represents a pathogenically important process. Previous studies have shown that microglial inhibitors can exert neuroprotective effects in HIE; however, the specific mechanisms underlying these effects have not yet been elucidated. Ligation of the left common carotid artery and exposure to 5% O₂ were utilized to produce an HIE model in rats. A number of experimental approaches were then used to determine the effect of a microglial inhibition, achieved via the administration of GW2580, a Csf1r inhibitor, and investigate the mechanisms involved. Our HIE models exhibited substantial brain infarction and were significantly impaired in motor functions (p < 0.01-0.001, in all tests examined). In the infarction areas, the number of microglia, macrophages, and neural stem cells (NSCs) was all dramatically increased over that in sham-injured rats, respectively (p < 0.05-0.001). The administration of GW2580 significantly reduced the numbers of microglia and macrophages, but increased the number of NSCs when compared to those in vehicle-treated HIE models (p < 0.05-0.001). Furthermore, GW2580 significantly ameliorated both the histological and behavioral phenotypes in HIE rats and increased STAT phosphorylation (p < 0.05-0.001). Finally, the inhibition or activation of STAT3 respectively decreased or increased the neuroprotective effects of GW2580 (p < 0.05-0.001). Collectively, our findings demonstrate that the STAT3 signaling pathway plays a critical role in the neuroprotective effects of microglial inhibition and may facilitate the development of novel therapeutic strategies to treat stroke.