1. Academic Validation
  2. Melatonin receptor agonist ramelteon attenuates mouse acute and chronic ischemic brain injury

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

  • Acta Pharmacol Sin. 2020 Aug;41(8):1016-1024. doi: 10.1038/s41401-020-0361-2.
Xiao-Li Wu  # 1 Shou-Sheng Lu  # 1 2 Meng-Ru Liu 1 Wei-Dong Tang 1 Jun-Zi Chen 3 Yan-Rong Zheng 1 Anil Ahsan 1 Ming Cao 1 Lei Jiang 1 Wei-Wei Hu 1 Jia-Ying Wu 1 Zhong Chen 4 Xiang-Nan Zhang 5
Affiliations

Affiliations

  • 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.
  • 4 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. [email protected].
  • 5 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. [email protected].
  • # Contributed equally.
Abstract

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

autophagy; cerebral ischemia; middle cerebral artery occlusion (MCAO); photothrombosis; melatonin receptors; ramelteon.

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