title: Aquaporin-4 as a New Target against Methamphetamine-Induced Brain Alterations: Focus on the Neurogliovascular Unit and Motivational Behavior.
abstract: Methamphetamine (METH) abuse/misuse is a worldwide problem, and despite extensive characterization of its neurotoxicity over the last years, many questions remain unanswered. Recently, it was shown that METH compromises the blood-brain barrier (BBB) and causes a disturbance in the water homeostasis leading to brain edema. Importantly, water transport at BBB is regulated by water channels, aquaporins (AQPs), with AQP4 being expressed in astrocytic end-feet surrounding brain endothelium. Thus, the main goal of this work was to unravel the role of AQP4 under conditions of METH consumption. Our results show that METH (4× 10 mg/kg, 2 h apart, i.p.) interferes with AQP4 protein levels causing brain edema and BBB breakdown in both mice striatum and hippocampus, which culminated in locomotor and motivational impairment. Furthermore, these effects were prevented by pharmacological blockade of AQP4 with a specific inhibitor (TGN-020). Moreover, siRNA knockdown of this water channel protected astrocytes from METH-induced swelling and morphologic alterations. Herein, we unraveled AQP4 as a new therapeutic target to prevent the negative impact of METH.
authors.affiliation: Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Subunit 1 - Polo 3, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Ricardo Alexandre
authors.initials: RA
authors.lastname: Leitão
authors.affiliation: CNC.IBILI, University of Coimbra, Coimbra, Portugal.|Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Sereno
authors.affiliation: CNC.IBILI, University of Coimbra, Coimbra, Portugal.|Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
authors.forename: João Miguel
authors.initials: JM
authors.lastname: Castelhano
authors.affiliation: CNC.IBILI, University of Coimbra, Coimbra, Portugal.|Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
authors.forename: Sónia Isabel
authors.initials: SI
authors.lastname: Gonçalves
authors.affiliation: Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Subunit 1 - Polo 3, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Coelho-Santos
authors.affiliation: Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Subunit 1 - Polo 3, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fontes-Ribeiro
authors.affiliation: CNC.IBILI, University of Coimbra, Coimbra, Portugal.|Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Castelo-Branco
authors.affiliation: Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Subunit 1 - Polo 3, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal. apmartins@fmed.uc.pt.|CNC.IBILI, University of Coimbra, Coimbra, Portugal. apmartins@fmed.uc.pt.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Silva
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001929:Brain Edema / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D008694:Methamphetamine / Q000633:toxicity; D051379:Mice; D009042:Motivation / Q000187:drug effects / Q000502:physiology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013830:Thiadiazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C558003:2-(nicotinamide)-1,3,4-thiadiazole; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D013830:Thiadiazoles; D009536:Niacinamide; D008694:Methamphetamine
keywords: Aquaporin-4; Astrocytes; Blood-brain barrier; Brain edema; Methamphetamine; Motivational behavior