PMID- 24948063 OWN - NLM STAT- MEDLINE DCOM- 20150212 LR - 20200106 IS - 2299-5684 (Electronic) IS - 1734-1140 (Linking) VI - 66 IP - 4 DP - 2014 Aug TI - Metrifonate, like acetylcholine, up-regulates neurotrophic activity of cultured rat astrocytes. PG - 618-23 LID - S1734-1140(14)00158-3 [pii] LID - 10.1016/j.pharep.2014.02.025 [doi] AB - BACKGROUND: Metrifonate is an inhibitor of acetylcholinesterase (AChE). Several studies confirmed its positive effects on cognitive impairment in Alzheimer's disease but it was due to adverse events withdrawn from clinical trials. Based on the importance of astrocytes in physiological and pathological brain activities we investigated the impact of metrifonate and, for comparison, acetylcholine on intrinsic neurotrophic activity in these cells. METHODS: Metabolic activity, intracellular adenosine 5'-triphosphate (ATP) levels and lactate dehydrogenase (LDH) release was measured to examine the impact of metrifonate on viability and integrity of cultured rat cortical astrocytes. The influence of metrifonate, acetylcholine and selective cholinergic ligands on nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) synthesis and secretion was determined by specific two-site enzyme immunoassays. RESULTS: Exposure of cultured astrocytes to metrifonate displayed no toxic effects on cell viability. Metrifonate and acetylcholine potently and transiently elevated NGF and BDNF, but not NT-3, protein levels and secretion with different intensity and time frame of their maximal response. Stimulatory effect on NGF was mimicked by selective nicotinic receptor agonist nicotine and completely blocked by nicotinic antagonist mecamylamine. The impact on BDNF synthesis was mimicked by muscarinic receptor agonist pilocarpine and abolished by selective muscarinic antagonist scopolamine. CONCLUSIONS: Metrifonate up-regulates astrocytic NGF and BDNF synthesis in the same manner as acetylcholine, their effect depends on different cholinergic pathways. These results suggest a trophic role of metrifonate, based on a well-known neurotrophic activity of NGF and BDNF in vivo. CI - Copyright (c) 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. FAU - Mele, Tina AU - Mele T AD - Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. FAU - Juric, Damijana Mojca AU - Juric DM AD - Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. Electronic address: damijana-mojca.juric@mf.uni-lj.si. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140426 PL - Switzerland TA - Pharmacol Rep JT - Pharmacological reports : PR JID - 101234999 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cholinergic Agonists) RN - 0 (Cholinesterase Inhibitors) RN - 9061-61-4 (Nerve Growth Factor) RN - DBF2DG4G2K (Trichlorfon) RN - N9YNS0M02X (Acetylcholine) SB - IM MH - Acetylcholine/*pharmacology MH - Animals MH - Animals, Newborn MH - Astrocytes/*drug effects/metabolism MH - Brain-Derived Neurotrophic Factor/biosynthesis MH - Cell Survival/drug effects MH - Cells, Cultured MH - Cholinergic Agonists/*pharmacology MH - Cholinesterase Inhibitors/*pharmacology MH - Nerve Growth Factor/*biosynthesis MH - Primary Cell Culture MH - Rats, Wistar MH - Trichlorfon/*pharmacology MH - Up-Regulation OTO - NOTNLM OT - Acetylcholine OT - Acetylcholine receptor OT - Astrocytes OT - Metrifonate OT - Neurotrophin EDAT- 2014/06/21 06:00 MHDA- 2015/02/13 06:00 CRDT- 2014/06/21 06:00 PHST- 2013/07/30 00:00 [received] PHST- 2014/02/03 00:00 [revised] PHST- 2014/02/26 00:00 [accepted] PHST- 2014/06/21 06:00 [entrez] PHST- 2014/06/21 06:00 [pubmed] PHST- 2015/02/13 06:00 [medline] AID - S1734-1140(14)00158-3 [pii] AID - 10.1016/j.pharep.2014.02.025 [doi] PST - ppublish SO - Pharmacol Rep. 2014 Aug;66(4):618-23. doi: 10.1016/j.pharep.2014.02.025. Epub 2014 Apr 26.