Fluvastatin protects cochleae from damage by high-level noise

Abstract

Exposure to noise and ototoxic drugs are responsible for much of the debilitating hearing loss experienced by about 350 million people worldwide. Beyond hearing aids and cochlear implants, there have been no other FDA approved drug interventions established in the clinic that would either protect or reverse the effects of hearing loss. Using Auditory Brainstem Responses (ABR) in a guinea pig model, we demonstrate that fluvastatin, an inhibitor of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, protects against loss of cochlear function initiated by high intensity noise. A novel synchrotron radiation based X-ray tomographic method that imaged soft tissues at micrometer resolution in unsectioned cochleae, allowed an efficient, qualitative evaluation of the three-dimensional internal structure of the intact organ. For quantitative measures, plastic embedded cochleae were sectioned followed by hair cell counting. Protection in noise-exposed cochleae is associated with retention of inner and outer hair cells. This study demonstrates the potential of HMG-CoA reductase inhibitors, already vetted in human medicine for other purposes, to protect against noise induced hearing loss.

Evidence Supporting the Hypothesis That Inflammation-Induced Vasospasm Is Involved in the Pathogenesis of Acquired Sensorineural Hearing Loss

“…In rats, atorvastatin was able to prevent noise-induced SNHL [90]. The same was found in mice [91] and more recently in guinea pigs [92]. In a prospective study of 84 hyperlipidemic patients and audiological assessment before and 6 months after commencement of a statin, a significant reduction of the hearing threshold at 6000 Hz was found and a significantly improved speech discrimination as well as a significant reduction in tinnitus frequency, duration, and severity and degree of annoyance [93].…”

Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

“…This is consistent with the known mechanism of action of nitrogencontaining bisphosphonates, which act on the mevalonatecholesterol pathway by inhibiting FPPS (Figure 5). Supporting a role for the mevalonate pathway, previous work has shown that inhibiting HMG-CoA reductase, which is further upstream in the mevalonate pathway, protected against noise-induced hearing loss in guinea pigs and mice (Park et al, 2012;Richter et al, 2018). Cholesterol metabolism is important in neurodegenerative diseases and strongly associated with SNHL (Malgrange et al, 2015).…”

Naringin attenuates cisplatin‐ and aminoglycoside‐induced hair cell injury in the zebrafish lateral line via multiple pathways

“…A recent interview‐based report showed that doctors tended to consider alternative medicines if ototoxicity is detected in patients 7 . However, ototoxic drugs are still widely used in most developing countries, due to economic conditions and no prescription‐restriction 8 . Therefore, reducing the ototoxicity of clinical drugs while ensuring their therapeutic efficacy is a problem that needs to be solved at present.…”