Combined antioxidants and anti-inflammatory therapies fail to attenuate the early and late phases of cyclodextrin-induced cochlear damage and hearing loss

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A major side effect of using high doses of HPβCD to treat Niemann Pick type C (NPC1) disease is sensorineural hearing loss caused by early damage to outer hair cells (OHCs) followed by a second wave of damage to inner hair cells (IHCs), pillar cells (PCs) and collapse of the sensory epithelium. Because oxidative stress and neuroinflammation were presumed to be causal mechanisms contributing to the slowly developing IHC and PC lesions that emerged between 4 and 8 weeks after HPβCD treatment, it was investigated whether combined anti-inflammatory and antioxidant therapy with MIN+HK-2 or MIN+NAC could be beneficial in protecting the IHCs and PCs from cyclodextrin ototoxicity. Combination 1 consisted of minocyclin (MIN), an antibiotic that suppresses neuroinflammation, and HK-2, a multifunctional redox modulator that suppresses oxidative stress. Combination 2 was comprised of minocycline plus N-acetyl cysteine (NAC), which upregulates glutathione, a potent antioxidant . However, neither combination therapy prevented the HPβCD-induced functional losses and neither prevented the degeneration of IHCs and PCs and formation of a flattened squamous sensory epithelium.

Senthilvelan Manohar, Dalian Ding, Haiyan Jiang, Li Li, Guang-Di Chen, Peter Kador, Richard Salvi,
Combined antioxidants and anti-inflammatory therapies fail to attenuate the early and late phases of cyclodextrin-induced cochlear damage and hearing loss, Hearing Research, 414, 2022, 108409,
https://doi.org/10.1016/j.heares.2021.108409.

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