7,8,3′-Trihydroxyflavone, a potent small molecule TrkB receptor agonist, protects spiral ganglion neurons from degeneration both in vitro and in vivo

Most sensorineural hearing loss cases occur as a result of hair cell loss, which results in secondary degeneration of spiral ganglion neurons (SGNs). Substantial loss of SGNs reduces the benefit of cochlear implants, which rely on SGNs for transmitting signals to the central auditory centers. Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) play essential roles in cochlear development and are required for SGN survival. Here we report that 7,8,3′-trihydroxyflavone (7,8,3′-THF), which is a small molecule agonist of tyrosine receptor kinase B (TrkB), promoted SGN survival with high potency both in vitro and in vivo. The compound protected the SGNs in a TrkB-dependent manner, as its effects on SGNs disappeared when the TrkB was blocked. Application of 7,8,3′-THF in the bulla of conditional connexin26 (cCx26)-null mice dramatically rescued SGNs in the applied ear compared to untreated control cochlea in the same animal. Our findings suggest that 7,8,3′-THF is a promising therapeutic agent protecting the SGNs from degeneration both in vitro and in vivo.

► Neuroprotective effects of a novel small molecule TrkB agonist were examined. ► The compound protected the spiral ganglion neurons (SGNs) with high potency. ► The compound protected the neurons in a TrkB-dependent manner in vitro. ► The rescued SGNs were able to fire action potentials in response to current stimulation. ► The compound promoted neuronal survival in vivo in a mouse model of neuronal degeneration of SGNs.