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Development of a novel bisphosphonate-7,8-dihydroxyflavone (DHF) derivative for regeneration of spiral ganglion synapsesAAO-HNSF Herbert Silverstein Otology and Neurotology Research Award.
18 April 2018 (online)
Improving spiral ganglion neuron (SGN) survival, neurite outgrowth, and synaptogenesis may lead to significant gains for deaf and hearing-impaired patients. 7,8-dihydroxyflavone (DHF) is a small molecule that mimics the activity of brain-derived neurotrophic factor (BDNF), which is one of the two primary neurotrophins expressed in the cochlea.
Bisphosphonates avidly bind to bone minerals and we have previously shown that local delivery of bisphosphonate into the mammalian cochlea is non-ototoxic and leads to long-term binding in the modiolus. Our long-term goal is to assess the feasibility of exploiting the bone-binding properties of bisphosphonates to anchor DHF and other neurotrophic small molecules within cochlear bone, thereby providing a depot for locally enriched, sustained delivery. As an initial step, we describe the activity of a risedronate-DHF hybrid molecule to promote SGN neurite outgrowth and synaptogenesis.
Dissected SGNs or explants of neonatal cochleas were treated in vitro with Risedronate-DHF or controls. Immunohistochemistry using neural and synaptic markers confirmed neurite outgrowth and synaptogenesis.
The Ris-DHF hybrid molecule maintained ability to stimulate neurite outgrowth in SGN cultures significantly better than control molecules alone. In organ of Corti explant cultures, Ris-DHF stimulated synaptic regeneration.
A novel bisphosphonate-DHF hybrid molecule retains neurotrophic properties as measured by neurite outgrowth length and synaptic regeneration in vitro.