GLYMPHATIC FLUID PHARMACOLOGY: FACILITATION OF B-AMYLOID CLEARANCE

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Accumulating evidence has unequivocally shown that aquaporin-4 (AQP-4) mediated glymphatic flow (GF) is responsible for beta-amyloid clearance. Further, disturbance in GF plays a significant role in the pathogenesis of Alzheimer disease (AD) (Figure 1). Accordingly, pharmacological agents capable of AQP-4 facilitation have become intense targets of drug development for AD. Studies on the molecular mechanisms of water dynamics within the Virchow-Robin space indicate that AQP-4 activities are inhibited by higher proton density mediated by an V-ATPase like proton channel (J Neuroimg 2015;25:861, PLOS ONE 10(5): e0123708). Therefore, effective agents capable of facilitating AQP-4 and, hence, beta-amyloid clearance, that can be targeted for development fall into in three distinct categories, namely, vacuolar ATPase inhibitors, extracellular proton buffering substrates, and direct AQP-4 facilitators (Figure 2). Using an MRI molecular imaging technique capable of quantitative assessment of GF non-invasively in vivo, H2O17 JJ Vicinal Coupling Proton Exchange (H2O17-JJVCPE), we investigated the effects and potencies of agents in these three categories in mice. Mice under urethane anesthesia( 1.2 g/kg) were maintained at a rectal temperature of 37°C ± 0.5 and oxygen saturation (SpO2) of above 93% throughout the study. Effects on GF of various agents in the three categories, given either as a single parenteral dose or multiple daily oral doses (5 days prior to the study), were measured using H2O17-JJVCPE. A detailed description of H2O17-JJVCPE can be found elsewhere (NeuroReport 2014;25:39). A direct AQP-4 facilitator, TGN-073, (Drugs Future 2008;33:897) given as a single parenteral dose, and an extracellular proton buffer, guanidinoethyl sulphonate (GES) (NeuroReport 1993;4:1035) given orally, daily for five days, unequivocally exhibited significant facilitation of GF. Neither agent had any adverse effects on animals.