PMID- 29309751 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20181211 IS - 1090-2430 (Electronic) IS - 0014-4886 (Linking) VI - 302 DP - 2018 Apr TI - Activation of NPY-Y2 receptors ameliorates disease pathology in the R6/2 mouse and PC12 cell models of Huntington's disease. PG - 112-128 LID - S0014-4886(18)30001-3 [pii] LID - 10.1016/j.expneurol.2018.01.001 [doi] AB - Huntington's disease (HD) is a monogenic inherited polyglutamine-mediated neurodegenerative disorder for which effective therapies are currently unavailable. Neuropeptide Y (NPY) has been implicated as a potential therapeutic target in several neurodegenerative diseases, including HD. However, its mechanisms of action in the context of HD pathology remain unknown. Here, we investigated the beneficial effects of Y2 receptor (Y2R) activation with NPY or Y2R selective agonist NPY(13-36) in the R6/2 mouse and PC12 cell models of HD. Also, we explored the effects of selective pharmacological blockage of Y2R using selective non-peptide small molecule Y2R antagonist SF31 in vivo and in vitro. Our results showed that activation of Y2R with intranasal NPY or NPY(13-36) led to an improved motor function in R6/2 mice as revealed by rotarod performance, vertical pole test, and hindlimb clasping behaviour. Also, intranasal NPY or NPY(13-36) led to a decrease in aggregated mHtt and mediated increase in dopamine and cAMP-regulated phosphoprotein, 32kDa (DARPP-32), brain-derived neurotrophic factor (BDNF), and activated extracellular signal-regulated protein kinases (pERK1/2) levels in R6/2 mice. Intranasal NPY or NPY(13-36) had no effect on body weight but showed positive effects on survival in R6/2 mice. Furthermore, intranasal NPY or NPY(13-36) attenuated induction of proinflammatory cytokine and inflammatory mediators in R6/2 mice. In contrast, antagonizing by using SF31 exacerbates phenotypic severity in R6/2 mice and treatment effects with either intranasal NPY or NPY(13-36) were significantly blocked(.)In vitro, using inducible PC12/Htt(Q103-EGFP) cells, treatment with NPY or NPY(13-36) protected against mHtt-mediated neuromorphological defects (neurite length and soma area) and neurotoxicity but had no effect on mHtt inclusion body formation. Conversely, co-treatment with SF31 significantly inhibited these effects. Together, our findings extend previous evidence of the beneficial effects of NPY in R6/2 mice, and more importantly, suggest that targeted activation of Y2R receptor might be a promising disease-modifying target for HD and other neurodegenerative diseases. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Fatoba, Oluwaseun AU - Fatoba O AD - International Graduate School of Neuroscience, Ruhr-University Bochum, D-44780 Bochum, Germany; Department of Neuroimmunology, Center for Clinical Research, Ruhr-University Bochum, D-44780 Bochum, Germany. FAU - Kloster, Eugen AU - Kloster E AD - Department of Human Genetics, Ruhr-University Bochum, D-44780 Bochum, Germany. FAU - Reick, Christiane AU - Reick C AD - Department of Neuroimmunology, Center for Clinical Research, Ruhr-University Bochum, D-44780 Bochum, Germany. FAU - Saft, Carsten AU - Saft C AD - Department of Neuroimmunology, Center for Clinical Research, Ruhr-University Bochum, D-44780 Bochum, Germany; Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, D-44791 Bochum, Germany. FAU - Gold, Ralf AU - Gold R AD - International Graduate School of Neuroscience, Ruhr-University Bochum, D-44780 Bochum, Germany; Department of Neuroimmunology, Center for Clinical Research, Ruhr-University Bochum, D-44780 Bochum, Germany; Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, D-44791 Bochum, Germany. FAU - Epplen, Jorg T AU - Epplen JT AD - International Graduate School of Neuroscience, Ruhr-University Bochum, D-44780 Bochum, Germany; Department of Human Genetics, Ruhr-University Bochum, D-44780 Bochum, Germany. FAU - Arning, Larissa AU - Arning L AD - Department of Human Genetics, Ruhr-University Bochum, D-44780 Bochum, Germany. FAU - Ellrichmann, Gisa AU - Ellrichmann G AD - Department of Neuroimmunology, Center for Clinical Research, Ruhr-University Bochum, D-44780 Bochum, Germany; Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, D-44791 Bochum, Germany. Electronic address: gisa.ellrichmann@rub.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180106 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Dopamine and cAMP-Regulated Phosphoprotein 32) RN - 0 (Enzyme Inhibitors) RN - 0 (Fluoresceins) RN - 0 (HTT protein, human) RN - 0 (Huntingtin Protein) RN - 0 (Neuropeptide Y) RN - 0 (Peptide Fragments) RN - 0 (Receptors, Neuropeptide Y) RN - 0 (neuropeptide Y (13-36)) RN - 0 (neuropeptide Y2 receptor) RN - 3301-79-9 (6-carboxyfluorescein) SB - IM MH - Animals MH - Brain/metabolism/*pathology MH - Disease Models, Animal MH - Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism MH - Encephalitis/drug therapy/*etiology/genetics MH - Enzyme Inhibitors/pharmacology MH - Fluoresceins/pharmacokinetics MH - Gene Expression Regulation/drug effects/*genetics MH - Huntingtin Protein/genetics/metabolism MH - Huntington Disease/*complications/drug therapy/genetics/mortality MH - MAP Kinase Signaling System/drug effects/genetics MH - Mice MH - Mice, Transgenic MH - Motor Activity/drug effects/genetics MH - Muscle Strength/drug effects/genetics MH - Neuropeptide Y/therapeutic use MH - PC12 Cells/drug effects/metabolism MH - Peptide Fragments/therapeutic use MH - Psychomotor Disorders/drug therapy/etiology MH - Rats MH - Receptors, Neuropeptide Y/genetics/*metabolism MH - Trinucleotide Repeats/genetics OTO - NOTNLM OT - Huntington's disease OT - Immunomodulation OT - Neuroprotection OT - PC12/Htt(Q103-EGFP) cells, NPY-Y2 receptor OT - R6/2 mice EDAT- 2018/01/09 06:00 MHDA- 2018/12/12 06:00 CRDT- 2018/01/09 06:00 PHST- 2017/10/31 00:00 [received] PHST- 2017/12/27 00:00 [revised] PHST- 2018/01/02 00:00 [accepted] PHST- 2018/01/09 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] PHST- 2018/01/09 06:00 [entrez] AID - S0014-4886(18)30001-3 [pii] AID - 10.1016/j.expneurol.2018.01.001 [doi] PST - ppublish SO - Exp Neurol. 2018 Apr;302:112-128. doi: 10.1016/j.expneurol.2018.01.001. Epub 2018 Jan 6.