title: Activation of melatonin receptor (MT1/2) promotes P-gp transporter in methamphetamine-induced toxicity on primary rat brain microvascular endothelial cells.
abstract: Melatonin has been known as a neuroprotective agent for the central nervous system (CNS) and the blood-brain barrier (BBB), which is the primary structure that comes into contact with several neurotoxins including methamphetamine (METH). Previous studies have reported that the activation of melatonin receptors (MT1/2) by melatonin could protect against METH-induced toxicity in brain endothelial cells via several mechanisms. However, its effects on the P-glycoprotein (P-gp) transporter, the active efflux pump involved in cell homeostasis, are still unclear. Thus, this study investigated the role of melatonin and its receptors on the METH-impaired P-gp transporter in primary rat brain microvascular endothelial cells (BMVECs). The results showed that METH impaired the function of the P-gp transporter, significantly decreasing the efflux of Rho123 and P-gp expression, which caused a significant increase in the intracellular accumulation of Rho123, and these responses were reversed by the interaction of melatonin with its receptors. Blockade of the P-gp transporter by verapamil caused oxidative stress, apoptosis, and cell integrity impairment after METH treatment, and these effects could be reversed by melatonin. Our results, together with previous findings, suggest that the interaction of melatonin with its receptors protects against the effects of the METH-impaired P-gp transporter and that the protective role in METH-induced toxicity was at least partially mediated by the regulation of the P-gp transporter. Thus, melatonin and its receptors (MT1/2) are essential for protecting against BBB impairment caused by METH.
authors.affiliation: Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Pichaya
authors.initials: P
authors.lastname: Jumnongprakhon
authors.affiliation: Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Sivanan
authors.initials: S
authors.lastname: Sivasinprasasn
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Bangkok, Thailand; Center for Neuroscience, Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand; Chulabhorn Graduate Institute, Kamphaeng Phet 6 Road, Lak Si, Bangkok 10210, Thailand.
authors.forename: Piyarat
authors.initials: P
authors.lastname: Govitrapong
authors.affiliation: Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Chainarong
authors.initials: C
authors.lastname: Tocharus
authors.affiliation: Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: jtocharus@gmail.com.
authors.forename: Jiraporn
authors.initials: J
authors.lastname: Tocharus
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D008694:Methamphetamine / Q000633:toxicity*; D055806:Microvessels / Q000166:cytology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044122:Receptor, Melatonin, MT1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020112:Rhodamine 123 / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000697:Central Nervous System Stimulants; D018696:Neuroprotective Agents; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D014363:Tryptamines; C057154:luzindole; D020112:Rhodamine 123; D008694:Methamphetamine; D014700:Verapamil; D008550:Melatonin
keywords: Blood-brain barrier; Melatonin; Melatonin receptors; Methamphetamine; P-glycoprotein transporter