Aquaporin-4 as a New Target against Methamphetamine-Induced Brain Alterations: Focus on the Neurogliovascular Unit and Motivational Behavior

• Published in: Molecular neurobiology Vol. 55; no. 3; pp. 2056 - 2069
• Main Authors: Leitão, Ricardo Alexandre, Sereno, José, Castelhano, João Miguel, Gonçalves, Sónia Isabel, Coelho-Santos, Vanessa, Fontes-Ribeiro, Carlos, Castelo-Branco, Miguel, Silva, Ana Paula
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-03-2018; Springer Nature B.V
• Subjects: Animals; Aquaporin 4; Aquaporin 4 - antagonists & inhibitors; Aquaporin 4 - deficiency; Aquaporin 4 - metabolism; Astrocytes; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain Edema - metabolism; Brain Edema - pathology; Brain Edema - prevention & control; Cell Biology; Drug abuse; Edema; Endothelium; Homeostasis; Locomotion - drug effects; Locomotion - physiology; Male; Methamphetamine; Methamphetamine - toxicity; Mice; Motivation - drug effects; Motivation - physiology; Neostriatum; Neurobiology; Neuroglia - drug effects; Neuroglia - metabolism; Neuroglia - pathology; Neurology; Neurosciences; Neurotoxicity; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Niacinamide - therapeutic use; siRNA; Therapeutic applications; Thiadiazoles - pharmacology; Thiadiazoles - therapeutic use; Water transport; Motivational behavior; Brain edema; Aquaporin-4; Blood-brain barrier; Astrocytes; Methamphetamine
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-017-0439-0

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.