脳由来神経栄養因子類似作用をもつ7,8-Dihydroxyflavoneの経口投与による前庭障害治療

抄録

Bilateral vestibulopathy (BVP) is a debilitating condition characterized by persistent imbalance and a markedly increased risk of falls, resulting from bilateral loss of vestibular function. While vestibular rehabilitation remains the mainstay of treatment, its efficacy is often limited, and no pharmacological interventions with strong evidence have been established yet. Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), are known to play a crucial role in the development, maintenance, and regeneration of vestibular hair cells and their afferent neurons. However, clinical application of BDNF is hindered by its large molecular size, poor permeability across the blood-labyrinth barrier, and the need for invasive inner ear delivery.

7,8-Dihydroxyflavone (DHF), a small-molecule TrkB receptor agonist that mimics BDNF activity, offers a promising alternative. DHF is orally bioavailable, crosses the blood-labyrinth barrier, and activates major downstream signaling pathways (MAPK/ERK, PI3K/Akt, PLC-γ), thereby promoting hair cell regeneration, synaptic remodeling, and neuronal survival.

In a gentamicin-induced vestibular injury model in guinea pigs, oral administration of DHF significantly enhanced the regeneration of both type I and II vestibular hair cells, preserved afferent nerve fibers, and facilitated functional recovery, as confirmed by caloric testing and synaptic marker analysis. These findings suggest that DHF may represent a novel, non-invasive, systemically deliverable therapeutic strategy for vestibular dysfunction.

Further research is warranted to optimize the dosing, improve delivery systems, and evaluate the efficacy across different etiologies of vestibular diseases. Development of DHF-based therapy may contribute to establishment of a new treatment paradigm in the field of vestibular regenerative medicine.