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Perinatal asphyxia often results in neonatal cerebral hypoxia-ischemia (HI), which is associated with high mortality and severe long-term neurological deficits in newborns. Currently, there are no effective drugs to mitigate the functional impairments post-HI. Previous studies have shown that fibroblast growth factor 21 (FGF21) has a potential neuroprotective effect against brain injury. However, the effect of FGF21 on neonatal HI brain injury is unclear. In the present study, both in vivo and in vitro models were used to assess whether recombinant human FGF21 (rhFGF21) could exert a neuroprotective effect after HI and explore the associated mechanism. The results showed that the rhFGF21 treatment remarkably reduced the infarct volume, ameliorated the body weight and improved the tissue structure after HI in neonatal rats. In addition, the rhFGF21 treatment lengthened the running endurance times in the rotarod test and decreased the mean escape latencies and increased the number of platform crossings in the Morris water maze test at 21 d post-HI insult. In contrast, the FGFR1 inhibitor PD173074 and PI3K inhibitor LY294002 partially reversed these therapeutic effects. In isolated primary cortical neurons, the rhFGF21 treatment protected primary neurons from oxygen-glucose deprivation (OGD) insult by inhibiting neuronal apoptosis and promoting neuronal survival. Both our in vivo and in vitro results reveal that rhFGF21 could inhibit neuronal apoptosis by activating the PI3K/Akt signaling pathway via FGF21/FGFR1/β-klotho complex formation. Therefore, rhFGF21 may be a promising therapeutic agent for promoting functional recovery after HI-induced neonatal brain injury. • rhFGF21 reduces the brain infarct volume and ameliorates the histological structure. • rhFGF21 improves motor and learning disabilities in rats after hypoxia-ischemia. • rhFGF21 activates the PI3K/Akt pathway via FGFR1/β-klotho post hypoxia-ischemia. • rhFGF21 attenuates OGD-induced primary cortical neuronal death. • rhFGF21 protects neurons against OGD injury by inhibiting neuronal apoptosis. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic (HI) brain injury remains a devastating clinical disease associated with high mortality and lifetime disability. Neonatal HI injury damages the architecture of neurovascular unit (NVU), thus, therapy targeting the NVU may provide effective neuroprotection against HI. This study was designed to investigate whether fibroblast growth factor 10 (FGF10) protected the NVU against HI and afforded observable neuroprotection in a rat model of neonatal HI brain injury. The results showed that FGF10 treatment significantly reduced brain damage post HI, characterized by reduction in brain infarct volume and tissue loss. Further interesting findings showed that FGF10 treatment exerted neuroprotective effects on HI brain injury in neonate rats through protecting the NVU against HI, evidenced by inhibition of neuronal cell apoptosis, suppression of gliosis, and amelioration of blood-brain barrier disruption. Collectively, our study indicates that FGF10 treatment exhibits great potential for protecting NVU against HI and attenuates neonatal brain injury, suggesting a potential novel therapeutic agent to this disease. • FGF10 decreases neuronal death via inhibiting neuronal apoptosis • FGF10 attenuates the activation of microglia and astrocytes through modulating TLR4/NF-κB signaling pathway • FGF10 ameliorates blood-brain barrier disruption via reducing tight junction and adherens junction proteins degradation and pericytes loss • FGF10 exerts protective effects on the neurovascular unit in a rat model of neonatal HI brain injury. [ABSTRACT FROM AUTHOR]