7,8-dihydroxyflavone ameliorates cognitive and motor deficits in a Huntingtons disease mouse model through specific activation of the PLCγ1 pathway

García-Díaz Barriga, Gerardo; Giralt, Albert; Anglada-Huguet, Marta; Gaja-Capdevilla, Nuria; Orlandi, Javier G.; Soriano, Jordi; Canals, Josep-Maria; Alberch, Jordi

doi:10.1093/HMG/DDX198

Title

7,8-dihydroxyflavone ameliorates cognitive and motor deficits in a Huntingtons disease mouse model through specific activation of the PLCγ1 pathway

Author

García-Díaz Barriga, Gerardo

Giralt, Albert

Anglada-Huguet, Marta

Gaja-Capdevilla, Nuria

Orlandi, Javier G.

Soriano, Jordi

Canals, Josep-Maria

Alberch, Jordi

Abstract

Huntingtons 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 PLCγ1 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 PLCγ1 pathway, but pleiotropic effects of the drug also contribute to its therapeutic potential.

Language

English

Source (journal)

Human molecular genetics. - Oxford

Publication

Oxford : 2017

ISSN

0964-6906

DOI

10.1093/HMG/DDX198

Volume/pages

26 :16 (2017) , p. 3144-3160