Melatonin exerts neuroprotective effects in mice with spinal cord injury by activating the Nrf2/Keap1 signaling pathway via the MT2 receptor.

IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Liyan Yan, Xiaonan Han, Mingkang Zhang, Hongwei Kou, Hongjian Liu, Tian Cheng
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Abstract

Spinal cord injury (SCI) is a devastating event that often leads to severe disability, and effective treatments for SCI are currently limited. The present study investigated the potential effects and specific mechanisms of melatonin treatment in SCI. Mice were divided into Sham (Sham), Vehicle (Veh), Melatonin (Mel), and Melatonin + 4-phenyl-2-propionamidotetralin (4P-PDOT) (Mel + 4PP) groups based on randomized allocation. The expression of MT2 and the nuclear factor-erythroid 2-related factor 2 (Nrf2)/Keap1 signaling pathways were examined, along with oxidative stress indicators, inflammatory factors and GFAP-positive cells near the injury site. The polarization of microglial cells in different inflammatory microenvironments was also observed. Cell survival, motor function recovery and spinal cord tissue morphology were assessed using staining and Basso Mouse Scale scores. On day 7 after SCI, the results revealed that melatonin treatment increased MT2 protein expression and activated the Nrf2/Keap1 signaling pathway. It also reduced GFAP-positive cells, mitigated oxidative stress, and suppressed inflammatory responses around the injury site. Furthermore, melatonin treatment promoted the polarization of microglia toward the M2 type, increased the number of neutrophil-positive cells, and modulated the transcription of Bax and Bcl2 in the injured spinal cord. Melatonin treatment alleviated the severity of spinal injuries and facilitated functional recovery in mice with SCI. Notably, blocking MT2 with 4P-PDOT partially reversed the neuroprotective effects of melatonin in SCI, indicating that the activation of the MT2/Nrf2/Keap1 signaling pathway contributes to the neuroprotective properties of melatonin in SCI. The therapeutic and translational potentials of melatonin in SCI warrant further investigation.
褪黑激素通过 MT2 受体激活 Nrf2/Keap1 信号通路,对脊髓损伤小鼠发挥神经保护作用。
脊髓损伤(SCI)是一种破坏性事件,通常会导致严重残疾,而目前有效治疗脊髓损伤的方法有限。本研究调查了褪黑激素治疗 SCI 的潜在效果和具体机制。小鼠按随机分配法分为假阴性组(Sham)、车辆组(Veh)、褪黑素组(Mel)和褪黑素+4-苯基-2-丙脒基四氢萘组(4P-PDOT)(Mel + 4PP)。研究人员检测了MT2和核因子-红细胞2相关因子2(Nrf2)/Keap1信号通路的表达,以及氧化应激指标、炎症因子和损伤部位附近的GFAP阳性细胞。此外,还观察了不同炎症微环境下小胶质细胞的极化。细胞存活率、运动功能恢复和脊髓组织形态通过染色和巴索小鼠量表评分进行评估。结果显示,在脊髓损伤后第7天,褪黑素治疗增加了MT2蛋白的表达,并激活了Nrf2/Keap1信号通路。它还减少了GFAP阳性细胞,减轻了氧化应激,抑制了损伤部位周围的炎症反应。此外,褪黑激素治疗还能促进小胶质细胞向 M2 型极化,增加中性粒细胞阳性细胞的数量,并调节损伤脊髓中 Bax 和 Bcl2 的转录。褪黑激素治疗减轻了脊髓损伤的严重程度,促进了脊髓损伤小鼠的功能恢复。值得注意的是,用4P-PDOT阻断MT2可部分逆转褪黑激素对SCI的神经保护作用,这表明激活MT2/Nrf2/Keap1信号通路有助于褪黑激素对SCI的神经保护作用。褪黑激素在 SCI 中的治疗和转化潜力值得进一步研究。
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来源期刊
Experimental and therapeutic medicine
Experimental and therapeutic medicine MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
1.50
自引率
0.00%
发文量
570
审稿时长
1 months
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