Cochlear spiral ganglion neuron degeneration following cyclodextrin-induced hearing loss.

Because cyclodextrins are capable of removing cholesterol from cell membranes, there is growing interest in using these compounds to treat diseases linked to aberrant cholesterol metabolism. One compound, 2-hydroxypropyl-beta-cyclodextrin (HPβCD), is currently being evaluated as a treatment for Niemann-Pick Type C1 disease, a rare, fatal neurodegenerative disease caused by the buildup of lipids in endosomes and lysosomes. HPβCD can reduce some debilitating symptoms and extend life span, but the therapeutic doses used to treat the disease cause hearing loss. Initial studies in rodents suggested that HPβCD selectively damaged only cochlear outer hair cells during the first week post-treatment. However, our recent in vivo and in vitro studies suggested that the damage could become progressively worse and more extensive over time. To test this hypothesis, we treated rats subcutaneously with 1, 2, 3 or 4 g/kg of HPβCD and waited for 8-weeks to assess the long-term histological consequences. Our new results indicate that the two highest doses of HPβCD caused extensive damage not only to OHC, but also to inner hair cells, pillar cells and other support cells resulting in the collapse and flattening of the sensory epithelium. The 4 g/kg dose destroyed all the outer hair cells and three-fourths of the inner hair cells over the basal two-thirds of the cochlea and more than 85% of the nerve fibers in the habenula perforata and more than 80% of spiral ganglion neurons in the middle of basal turn of the cochlea. The mechanisms that lead to the delayed degeneration of inner hair cells, pillar cells, nerve fibers and spiral ganglion neurons remain poorly understood, but may be related to the loss of trophic support caused by the degeneration of sensory and/or support cells in the organ of Corti. Despite the massive damage to the cochlear sensory epithelium, the blood vessels in the stria vascularis and the vestibular hair cells in the utricle and saccule remained normal.