Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan; Department of Nursing, Asia University, Taichung 41354, Taiwan; Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen, Fujian 361000, China.
School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan; Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Biomed Pharmacother. 2021 Jul;139:111593. doi: 10.1016/j.biopha.2021.111593. Epub 2021 Apr 14.
Cerebral ischemic events, comprising of excitotoxicity, reactive oxygen production, and inflammation, adversely impact the metabolic-redox circuit in highly active neuronal metabolic profile which maintains energy-dependent brain activities. Therefore, we investigated neuro-regenerative potential of melatonin (Mel), a natural biomaterial secreted by pineal gland.
We specifically determined whether Mel could influence tunneling nanotubes (TNTs)-mediated transfer of functional mitochondria (Mito) which in turn may alter membrane potential, oxidative stress and apoptotic factors. In vitro studies assessed the effects of Mito on levels of cytochrome C, mitochondrial transfer, reactive oxygen species, membrane potential and mass, which were all further enhanced by Mel pre-treatment, whereas in vivo studies examined brain infarct area (BIA), neurological function, inflammation, brain edema and integrity of neurons and myelin sheath in control, ischemia stroke (IS), IS + Mito and IS + Mel-Mito group rats.
Results showed that Mel pre-treatment significantly increased mitochondrial transfer and antioxidants, and inhibited apoptosis. Mel-pretreated Mito also significantly reduced BIA with improved neurological function. Apoptotic, oxidative-stress, autophagic, mitochondrial/DNA-damaged biomarkers indices were also improved.
Conclusively, Mel is a potent biomaterial which could potentially impart neurogenesis through repairing impaired metabolic-redox circuit via enhanced TNT-mediated mitochondrial transfer, anti-oxidation, and anti-apoptotic activities in ischemia.
包括兴奋性毒性、活性氧产生和炎症在内的脑缺血事件会对高度活跃的神经元代谢状态下的代谢-氧化还原电路产生不利影响，而这种代谢状态是维持依赖能量的大脑活动所必需的。因此，我们研究了褪黑素（Mel）的神经再生潜力，Mel 是松果腺分泌的天然生物材料。
我们特别确定了 Mel 是否可以影响管状结构（TNTs）介导的功能性线粒体（Mito）的转移，而这种转移反过来又可能改变膜电位、氧化应激和凋亡因子。体外研究评估了 Mito 对细胞色素 C、线粒体转移、活性氧、膜电位和质量水平的影响，而 Mel 预处理进一步增强了这些影响，而体内研究则检测了控制组、缺血性中风（IS）组、IS+Mito 组和 IS+Mel-Mito 组大鼠的脑梗死面积（BIA）、神经功能、炎症、脑水肿以及神经元和髓鞘的完整性。
结果表明，Mel 预处理显著增加了线粒体转移和抗氧化剂，并抑制了细胞凋亡。Mel 预处理的 Mito 还显著减少了 BIA，改善了神经功能。凋亡、氧化应激、自噬、线粒体/DNA 损伤生物标志物指数也得到了改善。
总而言之，Mel 是一种有效的生物材料，通过增强 TNT 介导的线粒体转移、抗氧化和抗凋亡作用，修复受损的代谢-氧化还原电路，有可能在缺血中发挥神经发生作用。
