PMID- 28541476 OWN - NLM STAT- MEDLINE DCOM- 20180117 LR - 20180225 IS - 1460-2083 (Electronic) IS - 0964-6906 (Linking) VI - 26 IP - 16 DP - 2017 Aug 15 TI - 7,8-dihydroxyflavone ameliorates cognitive and motor deficits in a Huntington's disease mouse model through specific activation of the PLCgamma1 pathway. PG - 3144-3160 LID - 10.1093/hmg/ddx198 [doi] AB - Huntington's disease (HD) is a fatal neurodegenerative disease with motor, cognitive and psychiatric impairment. Dysfunctions in HD models have been related to reduced levels of striatal brain-derived neurotrophic factor (BDNF) and imbalance between its receptors TrkB and p75(NTR). Thus, molecules with activity on the BDNF/TrkB/p75 system can have therapeutic potential. 7,8-Dihydroxyflavone (7,8-DHF) was described as a TrkB agonist in several models of neuro-degenerative diseases, however, its TrkB activation profile needs further investigation due to its pleiotropic properties and divergence from BDNF effect. To investigate this, we used in vitro and in vivo models of HD to dissect TrkB activation upon 7,8-DHF treatment. 7,8-DHF treatment in primary cultures showed phosphorylation of TrkBY816 but not TrkBY515 with activation of the PLCgamma1 pathway leading to morphological and functional improvements. Chronic administration of 7,8-DHF delayed motor deficits in R6/1 mice and reversed deficits on the Novel Object Recognition Test (NORT) at 17 weeks. Morphological and biochemical analyses revealed improved striatal levels of enkephalin, and prevention of striatal volume loss. We found a TrkBY816 but not TrkBY515 phosphorylation recovery in striatum concordant with in vitro results. Additionally, 7,8-DHF normalized striatal levels of induced and neuronal nitric oxide synthase (iNOS and nNOS, respectively) and ameliorated the imbalance of p75/TrkB. Our results provide new insights into the mechanism of action of 7,8-DHF suggesting that its effect through the TrkB receptor in striatum is via selective phosphorylation of its Y816 residue and activation of PLCgamma1 pathway, but pleiotropic effects of the drug also contribute to its therapeutic potential. CI - (c) The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Garcia-Diaz Barriga, Gerardo AU - Garcia-Diaz Barriga G AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Giralt, Albert AU - Giralt A AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Anglada-Huguet, Marta AU - Anglada-Huguet M AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Gaja-Capdevila, Nuria AU - Gaja-Capdevila N AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Orlandi, Javier G AU - Orlandi JG AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Soriano, Jordi AU - Soriano J AD - Departament de Fisica de la Materia Condensada, Universitat de Barcelona, Barcelona, Spain. AD - Institute of Complex Systems (UBICS), Universitat de Barcelona, Barcelona, Spain. FAU - Canals, Josep-Maria AU - Canals JM AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Alberch, Jordi AU - Alberch J AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Hum Mol Genet JT - Human molecular genetics JID - 9208958 RN - 0 (6,7-dihydroxyflavone) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Flavones) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 3.1.4.3 (Phospholipase C gamma) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cognition/drug effects MH - Corpus Striatum/metabolism MH - Disease Models, Animal MH - Flavones/*metabolism/pharmacology/*therapeutic use MH - Hippocampus/metabolism MH - Huntington Disease/drug therapy/*metabolism MH - Mice MH - Mice, Transgenic MH - Motor Neurons/drug effects MH - Phospholipase C gamma/drug effects/metabolism MH - Phosphorylation MH - Receptor, trkB/metabolism MH - Signal Transduction/drug effects EDAT- 2017/05/26 06:00 MHDA- 2018/01/18 06:00 CRDT- 2017/05/26 06:00 PHST- 2017/04/11 00:00 [received] PHST- 2017/05/17 00:00 [accepted] PHST- 2017/05/26 06:00 [pubmed] PHST- 2018/01/18 06:00 [medline] PHST- 2017/05/26 06:00 [entrez] AID - 3852118 [pii] AID - 10.1093/hmg/ddx198 [doi] PST - ppublish SO - Hum Mol Genet. 2017 Aug 15;26(16):3144-3160. doi: 10.1093/hmg/ddx198.