Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Pediatrics, Division of Neonatology, Boston University School of Medicine, Boston, MA, USA.
J Pineal Res. 2018 Jan;64(1). doi: 10.1111/jpi.12443. Epub 2017 Oct 23.
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 MT1 receptors is reduced in newborn H-I brain injury and whether the protective action of melatonin is by alterations of the MT1 receptors. We demonstrated that there was significant reduction in MT1 receptors in ischemic brain of mouse pups in vivo following H-I brain injury and that melatonin offers neuroprotection through upregulation of MT1 receptors. The role of MT1 receptors was further supported by observation of increased mortality in MT1 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 MT1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation.
褪黑素作为一种保护新生儿缺氧缺血（H-I）脑损伤的物质的功能尚未得到充分研究，褪黑素在神经疾病中引起神经保护的机制仍在不断发展。本研究旨在探讨 MT1 受体的表达是否在新生儿 H-I 脑损伤中减少，以及褪黑素的保护作用是否通过改变 MT1 受体来实现。我们发现在新生鼠 H-I 脑损伤后，体内缺血脑组织中 MT1 受体明显减少，而褪黑素通过上调 MT1 受体提供神经保护作用。MT1 受体的作用进一步得到了支持，因为观察到在 H-I 脑损伤后，MT1 敲除小鼠的死亡率增加，以及褪黑素受体拮抗剂 luzindole 逆转了褪黑素对线粒体细胞死亡途径的抑制作用。这些数据表明，褪黑素通过恢复 MT1 受体、抑制线粒体细胞死亡途径和抑制星形胶质细胞和小胶质细胞的激活，介导其在新生鼠 H-I 脑损伤模型中的神经保护作用，至少部分是这样。
