Melatonin receptor agonist ramelteon attenuates mouse acute and chronic ischemic brain injury

Xiao-li Wu1, Shou-sheng Lu1,2, Meng-ru Liu1, Wei-dong Tang1, Jun-zi Chen3, Yan-rong Zheng1, Anil Ahsan1, Ming Cao1, Lei Jiang1, Wei-wei Hu1, Jia-ying Wu1, Zhong Chen and Xiang-nan Zhang1, Xiang-nan Zhang
1 Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou 310058, China
2 Department of Pharmacy, First People’s Hospital of Linhai City, Linhai 317000, China
3 Hangzhou No.4 High school, Hangzhou 310018, China
Correspondence to: Xiang-nan Zhang:,
DOI: 10.1038/s41401-020-0361-2
Received: 26 September 2019
Accepted: 2 January 2020
Advance online: 27 February 2020


Melatonin receptors (MTs) are potential drug targets for stroke therapy. Ramelteon is a selective melatonin receptor agonist used to treat insomnia. In this study we investigated whether ramelteon could attenuate cerebral ischemia in mice. Acute focal cerebral ischemia was induced in mice via middle cerebral artery occlusion (MCAO). We found oral administration of ramelteon (3.0 mg/kg) significantly attenuated ischemic injury even when it was given 4 h after the onset of ischemia. We showed that administration of ramelteon (3.0 mg/kg) displayed comparable protective efficacy and length of effective time window as administration of edaravone (10 mg/kg, i.p.), which was used in clinic to treat ischemic stroke. Chronic ischemic brain injury was induced in mice using photothrombosis. Oral administration of ramelteon (3.0 mg · kg−1 · d−1) for 7 days after ischemia significantly attenuated functional deficits for at least 15 days. The neuroprotection of ramelteon was blocked by 4-P-PDOT, a specific MT antagonist. We further revealed that ramelteon significantly inhibited autophagy in the peri-infarct cortex in both the mouse ischemia models via regulating AMPK/mTOR signaling pathway. Intracerebroventricular injection of rapamycin, an autophagy activator, compromised the neuroprotection of ramelteon, suggesting ramelteon might attenuate ischemic injury by counteracting autophagic cell death. These data demonstrate for the first time the potential benefits of ramelteon in the treatment of both acute and chronic ischemic brain injury and provide the rationale for the application of ramelteon in stroke therapy.
Keywords: cerebral ischemia; ramelteon; autophagy; middle cerebral artery occlusion (MCAO); photothrombosis; melatonin receptors

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