Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Neurosci Lett. 2023 Jan 31;795:137043. doi: 10.1016/j.neulet.2022.137043. Epub 2022 Dec 29.
Microglial activation is readily detected following cerebral ischemia/reperfusion-induced injury. Activated microglia polarize into either classic pro-inflammatory M1 or protective M2 microglia following ischemia/reperfusion-induced injury. Melatonin is protective immediately after ischemia/reperfusion-induced brain injury. However, the ability of melatonin to affect longer-term recovery from ischemic/reperfusion-induced injury as well as its ability to modulate microglia/macrophage polarization are unknown. The goal of this study is to understand the impact of melatonin on mice 14 days after injury, as well as to understand how melatonin affects microglial polarization of neuronal MT activation following cerebral ischemia/reperfusion. We utilized MT-GFP transgenic mice which overexpress MT (melatonin type 1 receptor) in neurons. Melatonin-treated or vehicle treated wild type and MT-GFP mice underwent middle cerebral artery occlusion (MCAO)/reperfusion and followed for 14 days. Neuronal MT overexpression significantly reduced infarct volumes, improved motor function, and ameliorated weight loss. Additionally, melatonin treatment reduced infarct volume in MT-GFP mice as compared to untreated wild type, melatonin treated wild type, and untreated MT-GFP mice. Melatonin improved neurological function and prevented weight loss in MT-GFP mice compared with melatonin treated wild type mice. Finally, melatonin treatment in combination with MT overexpression reduced the numbers of Iba1/CD16 M1 microglia and increased the numbers of Iba1/ CD206 M2 microglia after ischemic injury. In conclusion, neuronal MT mediates melatonin-induced long-term recovery after cerebral ischemia, at least in part, by shifting microglial polarization toward the neuroprotective M2 phenotype.
小胶质细胞激活在脑缺血/再灌注损伤后很容易被检测到。在缺血/再灌注损伤后，激活的小胶质细胞可极化为经典的促炎 M1 型或保护性 M2 型小胶质细胞。褪黑素在脑缺血/再灌注损伤后具有保护作用。然而，褪黑素对缺血/再灌注损伤后长期恢复的影响及其对小胶质细胞/巨噬细胞极化的调节能力尚不清楚。本研究的目的是了解褪黑素对损伤后 14 天的小鼠的影响，以及了解褪黑素如何影响脑缺血/再灌注后神经元 MT 激活的小胶质细胞极化。我们利用 MT-GFP 转基因小鼠，其在神经元中过度表达 MT（褪黑素 1 型受体）。用褪黑素处理或用载体处理野生型和 MT-GFP 小鼠，然后进行大脑中动脉闭塞（MCAO）/再灌注，并随访 14 天。神经元 MT 的过度表达显著减少梗死体积，改善运动功能，并减轻体重减轻。此外，与未处理的野生型、褪黑素处理的野生型和未处理的 MT-GFP 小鼠相比，褪黑素处理可减少 MT-GFP 小鼠的梗死体积。与褪黑素处理的野生型小鼠相比，褪黑素处理可改善 MT-GFP 小鼠的神经功能并防止体重减轻。最后，褪黑素治疗与 MT 过表达相结合，可减少缺血性损伤后 Iba1/CD16 M1 小胶质细胞的数量，并增加 Iba1/CD206 M2 小胶质细胞的数量。总之，神经元 MT 介导了褪黑素诱导的脑缺血后长期恢复，至少部分是通过将小胶质细胞极化向神经保护的 M2 表型转变。
