Apelin-13 ameliorates hypoxic-ischemic brain damage and improves neurological function in neonatal rats by attenuating neuroinflammation via AMPK activation.

BACKGROUND

Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is a severe neurological disorder in which neuroinflammation contributes substantially to secondary brain injury and functional impairment. Although apelin-13 has demonstrated anti-inflammatory and neuroprotective effects in central nervous system injury models, its role in modulating neuroinflammation following HIE remains poorly understood. This study aimed to investigate the anti-inflammatory effects of apelin-13 in HIE and to elucidate the underlying mechanisms.

METHODS

Neonatal rats were subjected to hypoxic-ischemic (HI) injury and administered apelin-13 and/or the adenosine monophosphate-activated protein kinase (AMPK) inhibitor Compound C (CC) intraperitoneally at designated time points. At 24 h post-HI, cerebral damage was assessed by magnetic resonance imaging (MRI) and histopathological examination. Neurological function and white matter integrity were evaluated using neurobehavioral tests and diffusion tensor imaging (DTI). Molecular mechanisms involving inflammation and apoptosis were analyzed by Western blot and immunofluorescence.

RESULTS

Apelin-13 treatment reduced cerebral infarct volume, improved neurological function, and attenuated neuronal damage and apoptosis. It suppressed neuroglial activation and downregulated IL-1β, TNF-α, and caspase-3 expression. DTI revealed improved white matter microstructural integrity across multiple brain regions following apelin-13 intervention. Furthermore, these protective effects were mediated through AMPK phosphorylation and were reversed upon co-treatment with the AMPK inhibitor CC.

CONCLUSIONS

Apelin-13 attenuated neuroinflammation, enhanced neurological function, and preserved white matter integrity in HI injury by promoting AMPK phosphorylation. These findings suggest that apelin-13 exerts potent neuroprotective effects against HI injury, identifying AMPK activation as a pivotal mechanism underlying this protection.