Microglial Polarization in Neonatal Hypoxic-Ischemic Encephalopathy: Roles and Therapeutic Potential

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and long-term neurological impairments. Apart from therapeutic hypothermia, there are currently no effective pharmacological treatments. Microglia, as the resident immune cells of the nervous system, play a critical role in the pathogenesis and subsequent neural repair processes of HIE. However, the exact mechanisms underlying these roles remain unclear, and potential therapeutic targets for modulating microglial polarization still need to be explored. Methods: This review outlines the physiological functions of microglia in the developing brain and the role of microglial polarization in neonatal HIE. It discusses several strategies for targeting the modulation of microglial polarization and their underlying molecular mechanisms. Results: Microglial activation is one of the core pathophysiological mechanisms of neonatal HIE. During the acute phase of hypoxic-ischemic injury, microglia are typically activated to an M1 pro-inflammatory phenotype, mediating inflammatory responses and exacerbating neuronal damage. Over time, some microglia transition into the M2 phenotype, where they play a role in tissue repair and neuroprotection. The balance between pro-inflammatory and anti-inflammatory microglial phenotypes plays a crucial role in determining the prognosis of neonatal HIE. Several interventions targeting the modulation of microglial polarization, including IL-4, miRNA, and cyclic GMP-AMP synthase (cGAS), have shown promising results in animal models. However, the therapeutic mechanisms and safety of these approaches still require further investigation. Conclusions: Understanding how to effectively regulate microglial phenotype polarization to maximize neuroprotective effects and promote brain repair holds significant potential for the treatment of neonatal HIE. This could help open new therapeutic avenues and improve the prognosis of affected infants.