Background: This study sought to investigate a novel effect of melatonin in reducing brain injury in an in vivo hyperglycemic intracerebral hemorrhage (ICH) model and further explore the mechanisms of protection.
Methods: Hyperglycemia ICH was induced in Sprague-Dawley rats by streptozocin injection followed by autologous blood injection into the striatum. A combined approach including RNA-specific depletion, electron microscopy, magnetic resonance, Western blots, and immunohistological staining was applied to quantify the brain injuries after ICH.
Results: Hyperglycemia resulted in enlarged hematoma volume, deteriorated brain edema, and aggravated neuronal mitochondria damage 3 days after ICH. Post-treatment with melatonin 2 hours after ICH dose-dependently improved neurological behavioral performance lasting out to 14 days after ICH. This improved neurological function was associated with enhanced structural and functional integrity of mitochondria. Mechanistic studies revealed that melatonin alleviated mitochondria damage in neurons via activating the PPARδ/PGC-1α pathway. Promisingly, melatonin treatment delayed until 6 hours after ICH still reduced brain edema and improved neurological functions. Melatonin supplementation reduces neuronal damage after hyperglycemic ICH by alleviating mitochondria damage in a PPARδ/PGC-1α-dependent manner.
Conclusion: Melatonin may represent a therapeutic strategy with a wide therapeutic window to reduce brain damage and improve long-term recovery after ICH.



中文翻译：

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褪黑激素可减轻高血糖大鼠脑出血后的神经元损伤。

背景：本研究旨在研究褪黑激素在体内高血糖脑出血 (ICH) 模型中减少脑损伤的新作用，并进一步探索保护机制。
方法：先给Sprague-Dawley大鼠注射链脲佐菌素，再将自体血注射到纹状体中，诱发高血糖ICH。应用包括 RNA 特异性耗竭、电子显微镜、磁共振、蛋白质印迹和免疫组织染色在内的组合方法来量化 ICH 后的脑损伤。
结果：ICH 后 3 天，高血糖导致血肿体积增大、脑水肿恶化和神经元线粒体损伤加重。ICH 后 2 小时使用褪黑激素进行后处理，以剂量依赖性方式改善神经行为表现，持续至 ICH 后 14 天。这种改善的神经功能与增强的线粒体结构和功能完整性有关。机制研究表明，褪黑激素通过激活 PPARδ/PGC-1α 通路来减轻神经元中的线粒体损伤。有希望的是，褪黑激素治疗延迟到 ICH 后 6 小时仍可减少脑水肿并改善神经功能。褪黑激素补充剂通过以 PPARδ/PGC-1α 依赖性方式减轻线粒体损伤来减少高血糖 ICH 后的神经元损伤。
结论：褪黑激素可能代表一种治疗策略，具有广泛的治疗窗口，可减少脑损伤并改善 ICH 后的长期恢复。