P49 Recurrent hypoglycaemia increases human primary astrocyte oxygen consumption, fatty acid dependency, and pentose phosphate pathway activityPG WEIGHTMAN POTTER1, JM Vlachaki Walker1, JL Robb1, J Chilton1, R Williamson2, A Randall3, KLJ Ellacott1, C Beall11Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, UK, 2School of Pharmacy and Medical Sciences, University of Bradford, Bradford, UK, 3Institute of Biomedical and Clinical Sciences, Hatherly Laboratories, University of Exeter Medical School, Exeter, UKRefer to Oral number A64P50Alzheimer's disease drug Memantine inhibits Adenosine triphosphate (ATP)‐sensitive potassium (KATP) channel activation in hypothalamic GT1‐7 cellsBC HALL1,2, C Beall1,2, AD Randall11Hatherly Laboratories, University of Exeter, Exeter, UK, 2Exeter Medical School, University of Exeter, Exeter, UKAims: KATP channels link cellular energy status to electrical activity in a variety of cell types, including pancreatic beta cells and neurons. In the brain, KATP channels are expressed abundantly in the hypothalamus, playing important roles in the regulation of energy metabolism. Memantine (Mem) is an uncompetitive weak N‐methyl‐D‐aspartate receptor (NMDA) antagonist used to treat Alzheimer's disease. Mem was recently reported to block recombinant KATP channels in the 10‐nM concentration range. This activity was suggested to contribute to Mem's therapeutic efficacy via actions at central nervous system (CNS) synapses. We have investigated the effect of Mem on the endogenous KATP channel conductance in the hypothalamic GT1‐7 cell line.Methods: Patch‐clamp electrophysiology at RT was used to examine whole cell currents after the cell had been dialysed with an ATP‐free pipette solution (ensuring KATP channels were maximally open, termed run‐up), Mem was applied via the perfusate.Results: Application of 100μM Mem after run‐up produced a significant reduction in whole‐cell leak conductance compared with vehicle (G/Gmax: Veh 0.86 ± 0.13 (n = 6), 100μM 0.38 ± 0.18 (n = 6), p < 0.05). Similarly, when Mem (100μM) was applied prior to ATP washout, a significant reduction in maximal conductance was observed at run‐up (nS/pF: Veh 1.06 ± 0.05 (n = 25), Mem 100μM 0.41 ± 0.02 (n = 7), p < 0.001). In both experimental protocols, neither 1μM nor 10μM Mem caused any significant reduction in leak current conductance compared with vehicle.Summary: Memantine reduces the leak conductance elicited by ATP washout in GT1‐7 cells; however, this is weak activity only being ˜60% complete at 100μM.
Diabetic Medicine – Wiley
Published: Jan 1, 2018
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