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Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1\u2010knockout (KO) mice and MT1\u2010KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene\u2010expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species\u2010induced oxidative stress and activates the nuclear factor erythroid 2\u2010related factor 2\/heme oxygenase\u20101 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1\u2010KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.<\/jats:p>","DOI":"10.1111\/jpi.12925","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T18:49:05Z","timestamp":1700678945000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The MT1 receptor as the target of ramelteon neuroprotection in ischemic stroke"],"prefix":"10.1111","volume":"76","author":[{"given":"Xinmu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Brigham and Women's Hospital, Harvard Medical School Boston Massachusetts USA"},{"name":"Department of Biopharmaceutical Sciences, College of Pharmacy Jilin University Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery 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