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M14 7,8 Dihydroxyflavone Ameliorates Cognitive And Motor Deficits In A Huntingon’s Disease Mouse Model Through A Different Activation Profile From Bdnf
  1. AGG Díaz Barriga,
  2. A Giralt,
  3. M Anglada-Huguet,
  4. JM Canals,
  5. J Alberch
  1. Departament Biologia Cellular, Immunologia i Neurociències Facultat de Medicina, Universitat de Barcelona-IDIBAPS

Abstract

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by an expanded CAG trinucleotide repeat in the gene encoding the protein huntingtin, it presents with abnormal motor coordination, cognitive decline and psychiatric disorders; the pathophysiology includes reduced levels of brain-derived neurotrophic factor (BDNF) in the brain; thus BDNF activation through its high-affinity receptor TrkB has become of interest for its therapeutic implications. 7,8-Dihydroxyflavone (7,8-DHF) has been described as a robust TrkB receptor agonist in a whole variety of in vitro models and tested on in vivo models of neurodegenerative diseases. Previously it has been described that chronic treatment with 7,8 DHF can ameliorate motor deficits in N171-82Q HD mice; here we tested its effects on cognitive and motor deficits on the R6/1 mouse model of HD. We found chronic treatment with 7,8 DHF is able to delay the onset of motor deficits in R6/1 mice assessed by the Rotarod test; furthermore 7,8 DHF reversed the inability to perform correctly the Novel Object Recognition Test (NORT) at 15 weeks; pathological and biochemical analyses of treated mice revealed improved levels of Enkephalin in striatum, (concordant with a trend on a DARPP32 recovery) and a reduction of striatal volume loss upon treatment. Interestingly in vivo results showed a TrkB Y816 but not TrkB Y515 phosphorylation recovery in striatum with acute and chronic treatment. 7,8 DHF treatment in primary neuronal cultures revealed the same differences in TrkB phosphorylation profile (selective phosphorylation of Y816 residues) and morphologic divergent changes from controls with BDNF. Our results suggest 7,8 DHF has therapeutic potential for HD but also that 7,8 DHF has differential effects from BDNF that should be further investigated.

KeyWords
  • TrkB Agonist
  • 7
  • 8 Dihydroxyflavone
  • BDNF
  • TrkB-phosphorylation

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