Dataset Information

Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning.

ABSTRACT: Despite increasing awareness of the many important roles played by brain-derived neurotrophic factor (BDNF) activation of TrkB, a fuller understanding of this system and the use of potential TrkB-acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB receptors in vivo. However, 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intraperitoneal administration. The authors combined pharmacological, biochemical, and behavioral approaches in a preclinical study examining the role of 7,8-DHF in modulating emotional memory in mice.The authors first examined the ability of systemic 7,8-DHF to activate TrkB receptors in the amygdala. They then examined the effects of systemic 7,8-DHF on acquisition and extinction of conditioned fear, using specific and well-characterized BDNF-dependent learning paradigms in several models using naive mice and mice with prior traumatic stress exposure.Amygdala TrkB receptors, which have previously been shown to be required for emotional learning, were activated by systemic 7,8-DHF (at 5 mg/kg i.p.). 7,8-DHF enhanced both the acquisition of fear and its extinction. It also appeared to rescue an extinction deficit in mice with a history of immobilization stress.These data suggest that 7,8-DHF may be an excellent agent for use in understanding the effects of TrkB activation in learning and memory paradigms and may be attractive for use in reversing learning and extinction deficits associated with psychopathology.

SUBMITTER: Andero R

PROVIDER: S-EPMC3770732 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning.

Andero Raul R Heldt Scott A SA Ye Keqiang K Liu Xia X Armario Antonio A Ressler Kerry J KJ

The American journal of psychiatry 20101201 2

<h4>Objective</h4>Despite increasing awareness of the many important roles played by brain-derived neurotrophic factor (BDNF) activation of TrkB, a fuller understanding of this system and the use of potential TrkB-acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB receptors in vivo. However, 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the b ...[more]

PMID: 21123312

Similar Datasets

Project description:Objective7,8-Dihydroxyflavone (7,8-DHF), a small molecular mimetic of brain-derived neurotrophic factor (BDNF), alleviates high-fat diet-induced obesity in female mice in a sex-specific manner by activating muscular tropomyosin-related kinase B (TrkB). However, the underlying molecular mechanism for this sex difference is unknown. Moreover, muscular estrogen receptor ? (ER?) plays a critical role in metabolic diseases. Impaired ER? action is often accompanied by metabolic syndrome (MetS) in postmenopausal women. This study investigated whether muscular ER? is involved in the metabolic effects of 7,8-DHF.MethodsFor the in vivo studies, 72 female C57BL/6J mice were given a low-fat diet or high-fat diet, and both received daily intragastric administration of vehicle or 7,8-DHF for 24 weeks. The hypothalamic-pituitary-ovarian (HPO) axis function was assessed by investigating typical sex-related serum hormones and the ovarian reserve. Indicators of menopausal MetS, including lipid metabolism, insulin sensitivity, bone density, and serum inflammatory cytokines, were also evaluated. The expression levels of ER? and other relevant signaling molecules were also examined. In vitro, the molecular mechanism involved in the interplay of ER? and TrkB receptors was verified in differentiated C2C12 myotubes using several inhibitors and a lentivirus short hairpin RNA-knockdown strategy.ResultsLong-term oral administration of 7,8-DHF acted as a protective factor for the female HPO axis function, protecting against ovarian failure, earlier menopause, and sex hormone disorders, which was paralleled by the alleviation of MetS coupled with the production of ER?-rich, TrkB-activated, and uncoupling protein 1 (UCP1) high thermogenic skeletal muscle tissues. 7,8-DHF-stimulated transactivation of ER? at serine 118 (S118) and tyrosine 537 (Y537), which was crucial to activate the BDNF/TrkB signaling cascades. In turn, activation of BDNF/TrkB signaling was also required for the ligand-independent activation of ER?, especially at the Y537 phosphorylation site. In addition, Src family kinases played a core role in the interplay of ER? and TrkB, synergistically activating the signaling pathways related to energy metabolism.ConclusionsThese findings revealed a novel role of 7,8-DHF in protecting the function of the female HPO axis and activating tissue-specific ER?, which improves our understanding of this sex difference in 7,8-DHF-mediated maintenance of metabolic homeostasis and provides new therapeutic strategies for managing MetS in women.

Dataset Information

Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning.

Publications

Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets