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

Abstract

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.

What is Normal? Neuromuscular junction reinnervation after nerve injury

“…This timeline is important when planning and interpreting experiments. English et al described similar results of low evoked gastrocnemius muscle maximal response amplitudes, at 10% to 30% of baseline, in C57BL/6J mice at 8 weeks after sciatic nerve cut and repair . After tibial nerve cut and repair in the NMRI mouse, in vitro evoked tetanic force in the soleus was noted to be low (54% of the uninjured side) at 4 weeks postinjury, but with nearly complete recovery (98% of the uninjured side) by 2 months postinjury .…”

Activation of Muscular TrkB by its Small Molecular Agonist 7,8-Dihydroxyflavone Sex-Dependently Regulates Energy Metabolism in Diet-Induced Obese Mice

“…7,8-DHF also displays impressive therapeutic efficacy in animal models of Parkinson disease (Jang et al, 2010), Alzheimer disease (Zhang et al, 2013), and Huntington disease (Jiang et al, 2013). Furthermore, 7,8-DHF demonstrates a promising effect in enhancing axon regeneration in BDNF conditional knockout (cKO) mice but not in TrkB cKO mice (English et al, 2013). These studies strongly support that 7,8-DHF is a bioavailable TrkB agonist, which could be used as a molecular tool to study the beneficial role of chronic TrkB activation in diseases such as obesity.…”

7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice

“…As a bioavailable chemical, 7,8-DHF can penetrate brain blood barrier upon intraperitoneal or oral administration to provoke TrkB and its downstream signaling, such as phosphoinositide 3-kinase/protein kinase B (Akt; Wu et al, 2014), to exert its central role in pathologic conditions. As a consequence of activating TrkB, 7,8-DHF inhibits obesity in female mice (Chan et al, 2015), reduces spine morphology abnormalities in fragile X syndrome (Tian et al, 2015), enhances axon regeneration and muscle renovation after peripheral nerves injuries (English et al, 2013), improves motor function and prolongs survival in Huntington’s disease (Jiang et al, 2013). Furthermore, it can reverse synapse loss and prevent memory deficits in Alzheimer’s disease (AD; Zhang et al, 2014a; Gao et al, 2016).…”