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7,8-Dihydroxyflavone, a Small Molecular Trkb Agonist, Is Useful for Treating Various BDNF-Implicated Human Disorders Chaoyang Liu1, Chi Bun Chan2 and Keqiang Ye3*

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7,8-Dihydroxyflavone, a Small Molecular Trkb Agonist, Is Useful for Treating Various BDNF-Implicated Human Disorders Chaoyang Liu1, Chi Bun Chan2 and Keqiang Ye3* Liu et al. Translational Neurodegeneration (2016) 5:2 DOI 10.1186/s40035-015-0048-7 REVIEW Open Access 7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders Chaoyang Liu1, Chi Bun Chan2 and Keqiang Ye3* Abstract Brain-derived neurotrophic factor (BDNF) regulates a variety of biological processes predominantly via binding to the transmembrane receptor tyrosine kinase TrkB. It is a potential therapeutic target in numerous neurological, mental and metabolic disorders. However, the lack of efficient means to deliver BDNF into the body imposes an insurmountable hurdle to its clinical application. To address this challenge, we initiated a cell-based drug screening to search for small molecules that act as the TrkB agonist. 7,8-Dihydroxyflavone (7,8-DHF) is our first reported small molecular TrkB agonist, which has now been extensively validated in various biochemical and cellular systems. Though binding to the extracellular domain of TrkB, 7,8-DHF triggers TrkB dimerization to induce the downstream signaling. Notably, 7,8-DHF is orally bioactive that can penetrate the brain blood barrier (BBB) to exert its neurotrophic activities in the central nervous system. Numerous reports suggest 7,8-DHF processes promising therapeutic efficacy in various animal disease models that are related to deficient BDNF signaling. In this review, we summarize our current knowledge on the binding activity and specificity, structure-activity relationship, pharmacokinetic and metabolism, and the pre-clinical efficacy of 7,8-DHF against some human diseases. Keywords: Flavonoids, Neurotrophin, BDNF, Mimetic compound, Receptor agonistic activity Background domain, resulting in activation of signaling pathways involv- Neurotrophins (NT) are growth factors that regulate the ing mitogen-activated protein kinase (MAPK), phos- development and maintenance of the peripheral and the phatidylinositol 3-kinase (PI3K) and phospholipase C-γ central nervous systems [1]. It is a family of secretary (PLC-γ). proteins that includes brain-derived neurotrophic factor BDNF is of particular therapeutic interest because of (BDNF), nerve growth factor (NGF), NT-3, and NT-4/ its neurotrophic actions on a number of neuronal popu- NT-5 [2]. BDNF exerts its biological functions on neu- lations including sensory neurons (implicated in periph- rons through two transmembrane receptors: the p75 eral sensory neuropathies [6]); motor neurons which are neurotrophin receptor (p75NTR) and the TrkB receptor degenerated in amyotrophic lateral sclerosis (ALS) [7]; tyrosine kinase, while NGF binds to TrkA, NT-4/5 binds dopaminergic neurons of the substantia nigra, which are to TrkB, and NT-3 preferentially binds to TrkC [3, 4]. lost in Parkinson’s disease (PD); and cholinergic neurons TrkB is one of the most widely distributed neurotrophic of the basal forebrain, that play a significant role in in receptors (NTRs) in the brain, which is highly enriched Alzheimer’s disease (AD) [8]. Moreover, BDNF protects in the neocortex, hippocampus, striatum, and brainstem hippocampal neurons from glutamate toxicity [9], rescues [5]. Binding of BDNF to TrkB receptor triggers its cerebellar neurons from programmed cell death [10], re- dimerization through conformational changes and auto- duces ischemic neuronal injury [11, 12] and improves phosphorylation of tyrosine residues in the intracellular functional recovery from postinjury regeneration [13]. Thus, BDNF may represent a beneficial therapeutic agent * Correspondence: [email protected] against a variety of human disorders such as ALS, AD, 3Department of Pathology and Laboratory Medicine, Emory University School PD, fetal alcohol exposure, autism and schizophrenia [14]. of Medicine, 615 Michael Street, Atlanta, GA 30322, USA However, the outcomes of several clinical trials using Full list of author information is available at the end of the article © 2015 Liu et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liu et al. Translational Neurodegeneration (2016) 5:2 Page 2 of 9 recombinant BDNF are disappointing [15, 16], possibly derived cell line T48 (which is stably transfected with because of the poor delivery and short in vivo half-life of TrkB) were utilized in our assay. We cultured the cells BDNF. In addition, BDNF binds to p75NTR, a promiscu- in 96-well plates and pre-incubated the cells with com- ous NTR that is known to activate cell death pathways via pounds from a library for 30 min, followed by stauros- recruitment of multiple adaptor proteins [17, 18]. To ad- porine (STS) treatment for 9 h. MR(DEVD)2 was dress these problems, tremendous effort has been made to introduced to the cells 1 h before examination under generate selective agonists of TrkB including monoclonal fluorescent microscope. The apoptotic cells could be de- antibodies [19] and peptide mimetics [20, 21] . Based on tected by the red signal, while the live cells had no sig- the fact that a monocyclic monomeric peptide resembling nal. Using this caspase-activated fluorescent dye as a the a single loop of BDNF (loop 2) acts as an inhibitor of visual assay, we screened thousands of compounds from BDNF-mediated neuronal survival, O’Leary and Hughes the Spectrum Collection library. Sixty-six compounds designed bicyclic dimeric peptides that mimic a pair of were found to selectively protect T48, but not SN56 solvent-exposed loops for the binding and activation of cells, from STS-initiated apoptosis, indicating that these TrkB. These dimeric peptides behave as partial agonists of compounds might act either directly through TrkB re- TrkB with respect to BDNF, which promotes the survival ceptor or its downstream signaling effectors. These posi- of embryonic chick sensory neurons in culture [20]. Re- tive hits were further analyzed on primary hippocampal cently, the tandem repeat peptide agonist approach has neurons for TrkB activation and neuronal survival. 7,8- been employed for designing BDNF/NT-4/5 mimetics but DHF is one of the positive compounds that specifically none of these peptidyl compound exhibit satisfactory in activate TrkB, but not TrkA or TrkC, at a concentration vivo agonistic effect on TrkB [22]. Adenosine and pituit- of 250 nM. It is also a bioavailable chemical that can ary adenylate cyclase-activating peptide (PACAP) has pass through the BBB to provoke TrkB and its down- also been reported to transactivate TrkB in cultured stream PI3K/Akt and MAPK activation in mouse brain hippocampal neurons, however, this G protein-coupled (cortex, hippocampus and hypothalamus) upon intraper- receptor ligand does not act as TrkB agonists as it only itoneal or oral administration. In addition to cortical and activates an immature form of TrkB after 1 h treatment hippocampal neurons, 7,8-DHF also protects other cell [23–25]. types including the RGC (retinal ganglion cells) and To search for small molecules that mimic the bio- PC12 cells from excitotoxic and oxidative stress-induced logical functions of BDNF, we developed a cell-based apoptosis and cell death [28–30]. Fitting with these in TrkB receptor-dependent survival assay system, and vitro neuroprotective actions, 7,8-DHF protects the used it to screen a chemical library via counter screen- RGC cells from excitotoxic and oxidative stress-induced ing. The positive hits were then subjected to TrkB activa- apoptosis in retinal glaucoma model in a TrkB- tion analysis in primary neurons and receptor binding dependent manner [28]. Moreover, 7,8-DHF promotes assays. Finally, we identified two lead compounds: 7,8-dihy- the survival and reduces apoptosis in cortical neurons of droxyflavone and deoxygedunin [26, 27], which bind to the TBI (traumatic brain injury) as administration of 7,8- receptor extracellular domain of TrkB, promote the recep- DHF at 3 h post-injury reduces brain tissue damage via tor dimerization and autophosphorylation, and activate the the PI3K/Akt pathway [31]. downstream signaling cascades. Due to its commercial To demonstrate that 7,8-DHF indeed is a TrkB specific availability, and the favorable chemical and physical charac- agonist, we performed in vitro filter binding assay with teristics, 7,8-DHF is has been extensively explored in a var- [3H]-labeled 7,8-DHF and purified recombinant TrkB iety of cell types and disease models since its first report in ECD (extracellular domain) proteins. We showed that 2010 [26]. In the current review, we will summarize the 7,8-DHF has a Kd of ~320 nM toward TrkB with a bind- main biochemical, physiological, pharmacological and func- ing ratio of 1:1 (ligand versus receptor). Similarly, Bio- tional activities of 7,8-DHF. Its therapeutic potentials core Surface Plasmon Resonance (SPR) and fluorescent against neurological and metabolic disorders will also be quenching assay support the notion that 7,8-DHF dir- discussed. ectly binds to TrkB ECD with Kd about 15.4 nM. As the positive control, BDNF displays a Kd of approximately Discovery of TrkB receptor agonists 1.7 nM. These assays also
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