Integrated stress response inhibition provides sex-dependent protection against noise-induced cochlear synaptopathy

Abstract

Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate levels of acoustic overstimulation associated with tinnitus and impaired speech perception cause cochlear synaptopathy, characterized physiologically by reduction in wave I of the suprathreshold auditory brainstem response (ABR) and reduced number of synapses between sensory hair cells and auditory neurons. The unfolded protein response (UPR), an endoplasmic reticulum stress response pathway, has been implicated in the pathogenesis and treatment of NIHL as well as neurodegeneration and synaptic damage in the brain. In this study, we used the small molecule UPR modulator Integrated Stress Response InhiBitor (ISRIB) to treat noise-induced cochlear synaptopathy in a mouse model. Mice pretreated with ISRIB prior to noise-exposure were protected against noise-induced synapse loss. Male, but not female, mice also exhibited ISRIB-mediated protection against noise-induced suprathreshold ABR wave-I amplitude reduction. Female mice had higher baseline wave-I amplitudes but greater sensitivity to noise-induced wave-I reduction. Our results suggest that the UPR is implicated in noise-induced cochlear synaptopathy, and can be targeted for treatment.

Estradiol Protects against Noise-Induced Hearing Loss and Modulates Auditory Physiology in Female Mice

“…The characterization of sex-differences in NIHL and ARHL-which share common mechanisms [78,79]-figures to bear heavily on the development of new therapeutics. In fact, previous reports already suggest that experimental NIHL therapeutics may exhibit sex-dependent efficacy [16,17]. Furthermore, existing FDA-approved, tissue-specific ESR2 modulators, like raloxifene (currently approved for treatment of osteoporosis in postmenopausal women), have been shown to confer neuroprotective effects in a mouse model of epilepsy [80], rendering such drugs as potential candidates for protection of hearing.…”

“…Next, we evaluated the effect of E 2 -replacement on ABR wave-1 amplitudes. A reduction in wave-1 amplitude in TTS-inducing noise exposure paradigms is used to indirectly assess the presence of cochlear synaptopathy, although recent studies demonstrate the potential for a reduction in wave-1 amplitude also in the absence of cochlear synaptopathy [17].…”

“…Finally, the most severe subtype of NIHL results in a permanent elevation of auditory thresholds-or permanent threshold shift (PTS)-with attendant damage to, or loss of, IHCs and OHCs. Following octave-band noise exposures, this loss often occurs half an octave above the noise band and in the more vulnerable basal portions of the cochlea, where basal OHCs display an intrinsic vulnerability to damage caused by free radicals compared to more apical OHCs [6,[12][13][14] While NIHL afflicts both males and females, recent evidence suggests that females display increased resilience to NIHL compared to males, and that this resilience may be mediated by estrogen signaling [15][16][17][18][19][20][21]. Recent findings from our laboratory demonstrate that gonadally intact female mice are relatively protected from a PTS-inducing noise exposure in comparison to gonadally intact males [16].…”

Sex-Linked Biology and Gender-Related Research Is Essential to Advancing Hearing Health

“…This pervasive practice enshrouds consequential sex-linked biological differences in physiology, injury response, and the efficacy of therapeutics that may affect the prevention, treatment, and management of disease. The recent increased focus on sex as a biological variable has uncovered numerous examples of differences in the response to injury, including injuries and pathologies of a neural etiology (Tierney et al 2017;Roy-O'Reilly & McCullough 2018;Yue et al 2019). Equally as important, abundant evidence demonstrates that sex-linked biology influences the efficacy of current therapeutics for injuries and pathologies of a neural etiology (Sramek et al 2016;Canevelli et al 2017;Nasser & Afify 2019).…”

“…Evidence also suggests that sex-linked biology may influence the efficacy of potential hearing loss therapeutics (Milon et al 2018; Rouse et al 2020). The observed sex-linked differences in susceptibility to NIHL and the efficacy of therapeutics may be activational and organizational [for an introduction to activational and organizational effects of hormones see McCarthy and Arnold (2011)].…”