PMID- 25661191
OWN - NLM
STAT- MEDLINE
DCOM- 20151001
LR  - 20181113
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1852
IP  - 5
DP  - 2015 May
TI  - Flavonoid derivative 7,8-DHF attenuates TBI pathology via TrkB activation.
PG  - 862-72
LID - S0925-4439(15)00050-2 [pii]
LID - 10.1016/j.bbadis.2015.01.018 [doi]
AB  - Traumatic brain injury (TBI) is followed by a state of metabolic dysfunction, 
      affecting the ability of neurons to use energy and support brain plasticity; 
      there is no effective therapy to counteract the TBI pathology. Brain-derived 
      neurotrophic factor (BDNF) has an exceptional capacity to support metabolism and 
      plasticity, which highly contrasts with its poor pharmacological profile. We 
      evaluated the action of a flavonoid derivative 7,8-dihydroxyflavone (7,8-DHF), a 
      BDNF receptor (TrkB) agonist with the pharmacological profile congruent for 
      potential human therapies. Treatment with 7,8-DHF (5mg/kg, ip, daily for 7 days) 
      was effective to ameliorate the effects of TBI on plasticity markers (CREB 
      phosphorylation, GAP-43 and syntaxin-3 levels) and memory function in Barnes maze 
      test. Treatment with 7,8-DHF restored the decrease in protein and phenotypic 
      expression of TrkB phosphorylation after TBI. In turn, intrahippocampal 
      injections of K252a, a TrkB antagonist, counteracted the 7,8-DHF induced TrkB 
      signaling activation and memory improvement in TBI, suggesting the pivotal role 
      of TrkB signaling in cognitive performance after brain injury. A potential action 
      of 7,8-DHF on cell energy homeostasis was corroborated by the normalization in 
      levels of PGC-1alpha, TFAM, COII, AMPK and SIRT1 in animals subjected to TBI. Results 
      suggest a potential mechanism by which 7,8-DHF counteracts TBI pathology via 
      activation of the TrkB receptor and engaging the interplay between cell energy 
      management and synaptic plasticity. Since metabolic dysfunction is an important 
      risk factor for the development of neurological and psychiatric disorders, these 
      results set a precedent for the therapeutic use of 7,8-DHF in a larger context.
CI  - Copyright (c) 2015 Elsevier B.V. All rights reserved.
FAU - Agrawal, Rahul
AU  - Agrawal R
AD  - Department of Integrative Biology & Physiology, University of California, Los 
      Angeles, CA, USA.
FAU - Noble, Emily
AU  - Noble E
AD  - Department of Integrative Biology & Physiology, University of California, Los 
      Angeles, CA, USA.
FAU - Tyagi, Ethika
AU  - Tyagi E
AD  - Department of Integrative Biology & Physiology, University of California, Los 
      Angeles, CA, USA.
FAU - Zhuang, Yumei
AU  - Zhuang Y
AD  - Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA, 
      USA.
FAU - Ying, Zhe
AU  - Ying Z
AD  - Department of Integrative Biology & Physiology, University of California, Los 
      Angeles, CA, USA.
FAU - Gomez-Pinilla, Fernando
AU  - Gomez-Pinilla F
AD  - Department of Integrative Biology & Physiology, University of California, Los 
      Angeles, CA, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, 
      Los Angeles, CA, USA. Electronic address: fgomezpi@ucla.edu.
LA  - eng
GR  - R01 NS050465/NS/NINDS NIH HHS/United States
GR  - R21 DA037689/DA/NIDA NIH HHS/United States
GR  - NS050465/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150203
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (6,7-dihydroxyflavone)
RN  - 0 (Carbazoles)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Flavones)
RN  - 0 (GAP-43 Protein)
RN  - 0 (Indole Alkaloids)
RN  - 0 (Qa-SNARE Proteins)
RN  - 97161-97-2 (staurosporine aglycone)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Animals
MH  - Brain Injuries/metabolism/physiopathology/*prevention & control
MH  - Carbazoles/pharmacology
MH  - Cognition Disorders/metabolism/physiopathology/prevention & control
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Energy Metabolism/drug effects
MH  - Flavones/*pharmacology
MH  - GAP-43 Protein/metabolism
MH  - Immunoblotting
MH  - Indole Alkaloids/pharmacology
MH  - Male
MH  - Maze Learning/drug effects
MH  - Memory/drug effects
MH  - Microscopy, Fluorescence
MH  - Mitochondria/drug effects/metabolism
MH  - Phosphorylation/drug effects
MH  - Qa-SNARE Proteins/metabolism
MH  - Rats, Sprague-Dawley
MH  - Receptor, trkB/*agonists/antagonists & inhibitors/metabolism
MH  - Signal Transduction/*drug effects
PMC - PMC4754355
MID - NIHMS665243
OTO - NOTNLM
OT  - 7,8-Dihydroxyflavone
OT  - Cognition
OT  - Metabolism
OT  - Plasticity
OT  - Traumatic brain injury
COIS- There is no conflict of interest for any of the contributing authors.
EDAT- 2015/02/11 06:00
MHDA- 2015/10/02 06:00
PMCR- 2016/05/01
CRDT- 2015/02/10 06:00
PHST- 2014/10/24 00:00 [received]
PHST- 2015/01/12 00:00 [revised]
PHST- 2015/01/21 00:00 [accepted]
PHST- 2015/02/10 06:00 [entrez]
PHST- 2015/02/11 06:00 [pubmed]
PHST- 2015/10/02 06:00 [medline]
PHST- 2016/05/01 00:00 [pmc-release]
AID - S0925-4439(15)00050-2 [pii]
AID - 10.1016/j.bbadis.2015.01.018 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2015 May;1852(5):862-72. doi: 10.1016/j.bbadis.2015.01.018. 
      Epub 2015 Feb 3.