A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone

Jang, Sung-Wuk; Liu, Xia; Yepes, Manuel; Shepherd, Kennie R.; Miller, Gary W.; Liu, Yang; Wilson, W. David; Xiao, Gui; Blanchi, Bruno; Sun, Yi; Ye, Keqiang

doi:10.1073/pnas.0913572107

Cited by 587 publications

(597 citation statements)

References 25 publications

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“…Because LTM in this test was especially impaired and because BDNF levels were reduced in the PC7 KO mice, we injected (i.p.) another cohort of mice 1 h before training with 0.7 mg/kg 7,8-dihydroxyflavone (DHF), a brain-penetrable BDNF receptor (TrkB) agonist (28,29). When tested 24 h after training, performance of the PC7 KO mice was virtually identical to that of the WT controls (Fig.…”

Section: Pc7 Ko Mice Are Deficient In Episodic Memory and A Trkb Agonistmentioning

confidence: 99%

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

Wetsel

Rodriguiz

Guillemot

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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PC7 belongs to the proprotein convertase family, whose members are implicated in the cleavage of secretory precursors. The in vivo function of PC7 is unknown. Herein, we find that the precursor proBDNF is processed into mature BDNF in COS-1 cells coexpressing proBDNF with either PC7 or Furin. Conversely, the processing of proBDNF into BDNF is markedly reduced in the absence of either Furin or PC7 in mouse primary hepatocytes. In vivo we observe that BDNF and PC7 mRNAs are colocalized in mouse hippocampus and amygdala and that mature BDNF protein levels are reduced in these brain areas in PC7 KO mice but not in the hippocampus of PC1/3 KO mice. Various behavioral tests reveal that in PC7 KO mice spatial memory is intact and plasticity of responding is mildly abnormal. Episodic and emotional memories are severely impaired, but both are rescued with the tyrosine receptor kinase B agonist 7,8-dihydroxyflavone. Altogether, these results support an in vivo role for PC7 in the regulation of certain types of cognitive performance, in part via proBDNF processing. Because polymorphic variants of human PC7 are being characterized, it will be important in future studies to determine their effects on additional physiological and behavioral processes.

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Section: Pc7 Ko Mice Are Deficient In Episodic Memory and A Trkb Agonistmentioning

confidence: 99%

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

Wetsel

Rodriguiz

Guillemot

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Two hours after the last administration, the mice were subjected to behavioral testing. The dosage of 5 mg/kg 7,8-DHF and a 2-h interval between the last drug treatment and assays were chosen on the basis of previous in vivo studies (Andero et al, 2010;Andero et al, 2011;Jang et al, 2010;Liu et al, 2010), which demonstrated central TrkB activation, enhanced neurogenesis, and related behavioral changes in mice or rats treated with systemic 7,8-DHF administration.…”

Section: Drug Treatmentsmentioning

confidence: 99%

“…or vehicle (17% DMSO) once daily for 10 consecutive days, and were tested with the spontaneous alternation Y-maze paradigm that assesses spatial working memory function (Lalonde, 2002;Ohno et al, 2004). The dosage of 7,8-DHF was determined based on previous in vivo studies demonstrating that systemic administration of this compound activates central TrkB receptors and rescues memory deficits in BDNF-knockout mice (Choi et al, 2010;Jang et al, 2010). A two-way ANOVA revealed a significant genotype Â drug interaction for the percent alternation performance (F(1, 28) ¼ 9.34, po0.05) with a significant main effect of drug (F(1, 28) ¼ 9.51, po0.05) (Figure 2a).…”

Section: Systemic 78-dhf Ameliorates Memory Deficits In 5xfad Micementioning

confidence: 99%

“…Remarkably, systemic administration of 7,8-DHF can activate TrkB receptors in brains as evidenced by increases in phosphorylated TrkB, and induce BDNF-like behavioral phenotypes such as enhanced learning and memory, and antistress or antidepressant-like effects in rodents (Andero et al, 2010;Andero et al, 2011;Choi et al, 2010;Jang et al, 2010;Liu et al, 2010). Therefore, the small-molecule TrkB receptor agonist 7,8-DHF represents a novel and useful tool to investigate the role of BDNFTrkB signaling in vivo.…”

Section: Introductionmentioning

confidence: 99%

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7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

Devi

Ohno

2011

Neuropsychopharmacol

244

179

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Increasing evidence suggests that reductions in brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) may have a role in the pathogenesis of Alzheimer's disease (AD). However, the efficacy and safety profile of BDNF therapy (eg, gene delivery) remains to be established toward clinical trials. Here, we evaluated the effects of 7,8-dihydroxyflavone (7,8-DHF), a recently identified small-molecule TrkB agonist that can pass the blood-brain barrier, in the 5XFAD transgenic mouse model of AD. 5XFAD mice at 12-15 months of age and non-transgenic littermate controls received systemic administration of 7,8-DHF (5 mg/kg, i.p.) once daily for 10 consecutive days. We found that 7,8-DHF rescued memory deficits of 5XFAD mice in the spontaneous alternation Y-maze task. 5XFAD mice showed impairments in the hippocampal BDNF-TrkB pathway, as evidenced by significant reductions in BDNF, TrkB receptors, and phosphorylated TrkB. 7,8-DHF restored deficient TrkB signaling in 5XFAD mice without affecting endogenous BDNF levels. Meanwhile, 5XFAD mice exhibited elevations in the b-secretase enzyme (BACE1) that initiates amyloid-b (Ab) generation, as observed in sporadic AD. Interestingly, 7,8-DHF blocked BACE1 elevations and lowered levels of the b-secretasecleaved C-terminal fragment of amyloid precursor protein (C99), Ab40, and Ab42 in 5XFAD mouse brains. Furthermore, BACE1 expression was decreased by 7,8-DHF in wild-type mice, suggesting that BDNF-TrkB signaling is also important for downregulating baseline levels of BACE1. Together, our findings indicate that TrkB activation with systemic 7,8-DHF can ameliorate AD-associated memory deficits, which may be, at least in part, attributable to reductions in BACE1 expression and b-amyloidogenesis.

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“…Two molecules have emerged from a screen for their cell survival promotion and cellsignaling properties. Both 7,8 dihydroxyflavone (7,8 DHF) (17) and deoxygedunin (18) have been shown to function as trkB agonists in vitro. Both molecules have been used to promote BDNFdependent activities in vivo (18)(19)(20).…”

mentioning

confidence: 99%

Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves

English¹,

Liu²,

Nicolini³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Treatments with two-small molecule tropomyosin receptor kinase B (trkB) ligands, 7,8 dihydroxyflavone (7,8 DHF) and deoxygedunin, were evaluated for their ability to promote the regeneration of cut axons in injured peripheral nerves in mice in which sensory and motor axons are marked by YFP. Peripheral nerves were cut and repaired with grafts from strain-matched, nonfluorescent donors and secured in place with fibrin glue. Lengths of profiles of regenerating YFP + axons were measured 2 wk later from confocal images. Axon regeneration was enhanced when the fibrin glue contained dilutions of 500-nM solution of either small-molecule trkB agonist. In mice in which the neurotrophin receptor trkB is knocked out selectively in neurons, axon regeneration is very weak, and topical treatment with 7,8 DHF had no effect on axon regeneration. Similar treatments with deoxygedunin had only a modest effect. In conditional BDNF knockout mice, topical treatments with either 7,8 DHF or deoxygedunin resulted in a reversal of the poor regeneration found in controls and produced significant enhancement of regeneration. In WT mice treated with 2 wk of daily i.p. injections of either 7,8 DHF or deoxygedunin (5 mg/kg), regenerating axon profiles were nearly twice as long as in controls. Restoration of direct muscle responses evoked by sciatic nerve stimulation to pretransection levels over an 8-wk survival period was found only in the treated mice. Treatments with either small-molecule trkB agonist enhanced axon regeneration and muscle reinnervation after peripheral nerve injuries.

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A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone

Cited by 587 publications

References 25 publications

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves

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