FGF21 Alleviates Hypoxic-Ischemic White Matter Injury in Neonatal Mice by Mediating Inflammation and Oxidative Stress Through PPAR-γ Signaling Pathway.

White matter injury (WMI), the most common type of brain damage in infants born preterm, is characterized by failure in oligodendrocyte progenitor cell maturation and myelination, thereby contributing to long-term neurological impairments. Regrettably, effective therapies for promoting remyelination and improving function are currently lacking for this growing population affected by WMI. Recombinant human fibroblast growth factor (rhFGF) 21 modulated microglial activation and then ameliorated brain damage and improved neurological deficits in several central nervous system diseases. However, the effects of rhFGF21 treatment on WMI in preterm infants remain uncertain. In this study, we established an in vivo mouse model of cerebral hypoxia-ischemia (HI)-induced brain WMI and an in vitro model using oxygen-glucose deprivation (OGD)-treated HMC3 cells to investigate the neuroprotective effects of rhFGF21 against WMI and elucidated the potential mechanism. Our findings demonstrated that administration of rhFGF21 significantly ameliorated the retardation of oligodendrocyte differentiation, promoted myelination, and mitigated axonal deficits, synaptic loss, and GFAP scarring, thereby improving lifelong cognitive and neurobehavioral dysfunction associated with WMI. Moreover, rhFGF21 modulated microglial polarization, promoted a shift from the M1 to the M2 microglial phenotype, and suppressed microglial activation, thus ameliorating inflammatory response and oxidative stress. Additionally, rhFGF21 treatment significantly inhibited the HMGB1/NF-κB pathway linked to inflammation, and activated the NRF2 pathway associated with oxidative stress through the upregulation of PPAR-γ. Importantly, the beneficial effects of rhFGF21 on HI-induced WMI and microglial activation were dramatically inhibited by PPAR-γ antagonist and its siRNA. Our findings provide compelling evidence that rhFGF21 treatment mitigated the inflammatory response and oxidative stress through the modulation of microglial polarization via the PPAR-γ-mediated HMGB1/NF-κB pathway and the NRF2 pathway, respectively, contributes to neuroprotection and the amelioration of WMI in neonatal mice. Thus, rhFGF21 represents a promising therapeutic agent for the treatment of neonatal WMI.