Melatonin Alleviates Neuronal Damage After Intracerebral Hemorrhage in Hyperglycemic Rats

Abstract

Feng Liang,1,* Jianli Wang,1,* Xiangyu Zhu,2,* Zhen Wang,1 Jingwei Zheng,1 Zeyu Sun,1 Shenbin Xu,1 Jianmin Zhang,1,3,4 Jingyi Zhou,1 Ligen Shi1 1Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 4Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ligen Shi 88 Jiefang Road, Hangzhou City, Zhejiang Province 310009, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected] Zhang 88 Jiefang Road, Hangzhou City, Zhejiang Province 310009, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]: 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.Keywords: melatonin, intracerebral hemorrhage, hyperglycemia, mitochondria, apoptosis

Keywords

• melatonin
• intracerebral hemorrhage
• hyperglycemia
• mitochondria
• apoptosis.