PMID- 28882412
OWN - NLM
STAT- MEDLINE
DCOM- 20171106
LR  - 20180419
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 298
IP  - Pt A
DP  - 2017 Dec
TI  - A flavonoid agonist of the TrkB receptor for BDNF improves hippocampal 
      neurogenesis and hippocampus-dependent memory in the Ts65Dn mouse model of DS.
PG  - 79-96
LID - S0014-4886(17)30223-6 [pii]
LID - 10.1016/j.expneurol.2017.08.018 [doi]
AB  - Intellectual disability is the unavoidable hallmark of Down syndrome (DS), with a 
      heavy impact on public health. Reduced neurogenesis and impaired neuron 
      maturation are considered major determinants of altered brain function in DS. 
      Since the DS brain starts at a disadvantage, attempts to rescue neurogenesis and 
      neuron maturation should take place as soon as possible. The brain-derived 
      neurotrophic factor (BDNF) is a neurotrophin that plays a key role in brain 
      development by specifically binding to tropomyosin-related kinase receptor B 
      (TrkB). Systemic BDNF administration is impracticable because BDNF has a poor 
      blood-brain barrier penetration. Recent screening of a chemical library has 
      identified a flavone derivative, 7,8-dihydroxyflavone (7,8-DHF), a small-molecule 
      that crosses the blood-brain barrier and binds with high affinity and specificity 
      to the TrkB receptor. The therapeutic potential of TrkB agonists for neurogenesis 
      improvement in DS has never been examined. The goal of our study was to establish 
      whether it is possible to restore brain development in the Ts65Dn mouse model of 
      DS by targeting the TrkB receptor with 7,8-DHF. Ts65Dn mice subcutaneously 
      injected with 7,8-DHF in the neonatal period P3-P15 exhibited a large increase in 
      the number of neural precursor cells in the dentate gyrus and restoration of 
      granule cell number, density of dendritic spines and levels of the presynaptic 
      protein synaptophysin. In order to establish the functional outcome of treatment, 
      mice were treated with 7,8-DHF from P3 to adolescence (P45-50) and were tested 
      with the Morris Water Maze. Treated Ts65Dn mice exhibited improvement of learning 
      and memory, indicating that the recovery of the hippocampal anatomy translated 
      into a functional rescue. Our study in a mouse model of DS provides novel 
      evidence that treatment with 7,8-DHF during the early postnatal period restores 
      the major trisomy-linked neurodevelopmental defects, suggesting that therapy with 
      7,8-DHF may represent a possible breakthrough for Down syndrome.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Stagni, Fiorenza
AU  - Stagni F
AD  - Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 
      Italy.
FAU - Giacomini, Andrea
AU  - Giacomini A
AD  - Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 
      Italy.
FAU - Guidi, Sandra
AU  - Guidi S
AD  - Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 
      Italy.
FAU - Emili, Marco
AU  - Emili M
AD  - Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 
      Italy.
FAU - Uguagliati, Beatrice
AU  - Uguagliati B
AD  - Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 
      Italy.
FAU - Salvalai, Maria Elisa
AU  - Salvalai ME
AD  - Department of Pharmaceutical Sciences, Amedeo Avogadro, University of Eastern 
      Piedmont, Italy.
FAU - Bortolotto, Valeria
AU  - Bortolotto V
AD  - Department of Pharmaceutical Sciences, Amedeo Avogadro, University of Eastern 
      Piedmont, Italy.
FAU - Grilli, Mariagrazia
AU  - Grilli M
AD  - Department of Pharmaceutical Sciences, Amedeo Avogadro, University of Eastern 
      Piedmont, Italy.
FAU - Rimondini, Roberto
AU  - Rimondini R
AD  - Department of Medical and Surgical Sciences, University of Bologna, Bologna, 
      Italy.
FAU - Bartesaghi, Renata
AU  - Bartesaghi R
AD  - Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 
      Italy. Electronic address: renata.bartesaghi@unibo.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170904
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (6,7-dihydroxyflavone)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Flavones)
RN  - 0 (Flavonoids)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - *Brain-Derived Neurotrophic Factor/metabolism
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Down Syndrome/*drug therapy/metabolism/pathology
MH  - Female
MH  - Flavones/pharmacology/therapeutic use
MH  - Flavonoids/pharmacology/*therapeutic use
MH  - Hippocampus/*drug effects/pathology/physiology
MH  - Male
MH  - Memory/*drug effects/physiology
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neurogenesis/*drug effects/physiology
MH  - Pilot Projects
MH  - Receptor, trkB/*agonists/metabolism
OTO - NOTNLM
OT  - BDNF-TrkB system
OT  - Down syndrome
OT  - Hippocampus
OT  - Memory
OT  - Neurogenesis
OT  - Pharmacotherapy
EDAT- 2017/09/09 06:00
MHDA- 2017/11/07 06:00
CRDT- 2017/09/09 06:00
PHST- 2017/03/30 00:00 [received]
PHST- 2017/08/24 00:00 [revised]
PHST- 2017/08/31 00:00 [accepted]
PHST- 2017/09/09 06:00 [pubmed]
PHST- 2017/11/07 06:00 [medline]
PHST- 2017/09/09 06:00 [entrez]
AID - S0014-4886(17)30223-6 [pii]
AID - 10.1016/j.expneurol.2017.08.018 [doi]
PST - ppublish
SO  - Exp Neurol. 2017 Dec;298(Pt A):79-96. doi: 10.1016/j.expneurol.2017.08.018. Epub 
      2017 Sep 4.