Ototoxicity of cyclodextrin derivatives

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There are two possible mechanisms behind the ototoxicity of 2-hydroxypropyl-β-cyclodextrin (HPBCD) treatment.
One is : the possible interaction of HPBCD with a motor protein called prestin, or cholesterol rich environment of this protein. A publication by Takahashi et al [1] describes that single, high-dose administration of HPβCD results in outer hair cells death in prestin wildtype mice, whereas outer hair cells were largely spared in prestin knockout mice in the basal region, implicating prestin’s involvement in ototoxicity of HPβCD. This motor protein of the outer hair cells in inner ear of human cochlea, can interact with cholesterol in vitro, which suggest that HPβCD-induced ototoxicity may involve disruption of this cholesterol-prestin interaction. Please note that HPBCD has considerable affinity to cholesterol forming an inclusion complex with it. Time-lapse analysis revealed that outer hear cells isolated from wild type animals deteriorated upon HPβCD treatment, while those from prestin-knockout, tolerated well the same treatment.
Second possibility: is an assumed role of propyleneglycol in the ototoxic effect of HPBCD. HPBCD has a certain low level of residual propyleneglycol originated from the synthesis of this cyclodextrin derivative. HPBCD as an excipient can have this propylenegylcol residue, however, when it is used as an API, in gigadoses, it may have an untoward side effect. Massive, high dose and chronic treatments of HPBCD will continuously deliver low amounts of propyleneglycol. The ototoxicity of propyleneglycol has been known for decades, as the two references below indicate [2,3].  So this could be considered as a root cause of HPBCD’s side effect.

Despite of the above results, the untoward side effect of HPBCD treatments certainly needs further studies to explore the root cause of this phenomenon.

[1] Takahashi, S., Homma, K., Zhou, Y., Nishimura, S., Duan, C., Chen, J., Ahmad, A., Cheatham, M-A., Zheng, J.: Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-β-cyclodextrin is prestin-dependent in Scientific Reports | 6:21973 | DOI: 10.1038/srep21973,

[2] Morizono T, Paparella MM, Juhn SK.:Ototoxicity of propylene glycol in experimental animals.  Am J Otolaryngol. 1980 Nov;1(5):393-9. https://doi.org/10.1016/S0196-0709(80)80020-2

[3] Morizono, T., Johnstone, B.M. Ototoxicity of chloramphenicol ear drops with propylene glycol as solvent.  Medical Journal of Australia, 2(16), 634–638. doi:10.5694/j.1326-5377.1975.tb106157.x 

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