Protection of melatonin in experimental models of newborn hypoxic‐ischemic brain injury through MT1 receptor

Abstract The function of melatonin as a protective agent against newborn hypoxic‐ischemic (H‐I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases are still evolving. This study was designed to investigate whether expression of MT 1 receptors is reduced in newborn H‐I brain injury and whether the protective action of melatonin is by alterations of the MT 1 receptors. We demonstrated that there was significant reduction in MT 1 receptors in ischemic brain of mouse pups in vivo following H‐I brain injury and that melatonin offers neuroprotection through upregulation of MT 1 receptors. The role of MT 1 receptors was further supported by observation of increased mortality in MT 1 knockout mice following H‐I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H‐I brain injury, at least in part, by the restoration of MT 1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation.