The MT1 receptor as the target of ramelteon neuroprotection in ischemic stroke.

Publisher: Wiley Country of Publication: England NLM ID: 8504412 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-079X (Electronic) Linking ISSN: 07423098 NLM ISO Abbreviation: J Pineal Res Subsets: MEDLINE

Publication: : Oxford : Wiley
Original Publication: New York : Liss, c1984-

Ischemic Stroke*/drug therapy ; Neuroprotective Agents*/pharmacology ; Neuroprotective Agents*/therapeutic use ; Melatonin*/pharmacology ; Brain Ischemia*/drug therapy ; Stroke*/drug therapy ; Stroke*/genetics ; Indenes*; Animals ; Mice ; Receptor, Melatonin, MT1/agonists ; Neuroprotection ; Signal Transduction ; Mice, Knockout ; Infarction, Middle Cerebral Artery/drug therapy ; Infarction, Middle Cerebral Artery/metabolism

Stroke is the leading cause of death and disability worldwide. 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-knockout (KO) mice and MT1-KO 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-expression 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-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 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-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.
(© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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K01 NS055072 United States NS NINDS NIH HHS; R21 AA030087 United States AA NIAAA NIH HHS

Keywords: CBF; MRI; MT1 receptor; MT1−/− cultured neurons; MT1−/− mice; Nrf2/HO-1; ROS; Ramelteon; bioinformatics; ischemic stroke; mitochondrial and autophagic death pathways; p-eNOS/eNOS

901AS54I69 (ramelteon)
0 (Receptor, Melatonin, MT1)
0 (Neuroprotective Agents)
JL5DK93RCL (Melatonin)
0 (Indenes)

Date Created: 20231121 Date Completed: 20240122 Latest Revision: 20250104

20250114

PMC10872556

10.1111/jpi.12925

37986632