White matter injury in the neonatal hypoxic‐ischemic brain and potential therapies targeting microglia

Abstract Neonatal hypoxic–ischemic (H‐I) injury, which mainly causes neuronal damage and white matter injury (WMI), is among the predominant causes of infant morbidity (cerebral palsy, cognitive and persistent motor disabilities) and mortality. Disruptions to the oxygen and blood supply in the perinatal brain affect the cerebral microenvironment and may affect microglial activation, excitotoxicity, and oxidative stress. Microglia are significantly associated with axonal damage and myelinating oligodendrocytes, which are major pathological components of WMI. However, the effects of H‐I injury on microglial functions and underlying transformation mechanisms remain poorly understood. The historical perception that these cells are major risk factors for ischemic stroke has been questioned due to our improved understanding of the diversity of microglial phenotypes and their alterable functions, which exacerbate or attenuate injuries in different regions in response to environmental instability. Unfortunately, although therapeutic hypothermia is an efficient treatment, death and disability remain the prognosis for a large proportion of neonates with H‐I injury. Hence, novel neuroprotective therapies to treat WMI following H‐I injury are urgently needed. Here, we review microglial mechanisms that might occur in the developing brain due to neonatal H‐I injury and discuss whether microglia function as a double‐edged sword in WMI. Then, we emphasize microglial heterogeneity, notably at the single‐cell level, and sex‐specific effects on the etiology of neurological diseases. Finally, we discuss current knowledge of strategies aiming to improve microglia modulation and remyelination following neonatal H‐I injury. Overall, microglia‐targeted therapy might provide novel and valuable insights into the treatment of neonatal H‐I insult.