Noise-induced hearing loss in the 21^(st) century: A research and translational update

Millions of people worldwide are exposed to harmful levels of noise daily in their work and leisure environment. This makes noise-induced hearing loss(NIHL) a major occupational health risk globally. NIHL is the second most common form of acquired hearing loss after agerelated hearing loss and is itself a major contributing factor to presbycusis. Temporary threshold shifts, once thought to be relatively harmless and recoverable, are now known to cause permanent cochlear injury leading to permanent loss of hearing sensitivity. This article reviews the current understanding of the cellular and molecular pathophysiology of NIHL with latest findings from animal models. Therapeutic approaches to protect against or to mitigate NIHL are discussed based on their proposed action against these known mechanisms of cochlear injury. Successes in identifying genes that predispose individuals to NIHL by candidate gene association studies are discussed with matched gene knockout animal models. This links to exciting developments in experimental gene therapy to replace and regenerate lost hair cells and post-noise otoprotective therapies currently being investigated in clinical trials. The aim is to provide new insights into current and projected future strategies to manage NIHL; bench to bedside treatment is foreseeable in the next 5 to 10 years.

Noise-induced cochlear inflammation

Hearing loss is the most common sensory disability with considerable social and economic implications. According to recent World Health Organization estimates,360 million people worldwide suffer from moderate to profound hearing loss. Exposure to excessive noise is one of the major causes of sensorineural hearing loss,secondary only to age-related hearing loss(presbyacusis). Since cochlear tissues have limited abilities of repair and regeneration, this damage can be irreversible, leading to cochlear dysfunction and permanent hearing loss. Recent studies have shown that cochlear inflammation can be induced by noise exposure and contribute to the overall pathogenesis of cochlear injury and hearing loss. The cochlea is separated from the systemic circulation by the blood-labyrinth barrier,which is physiologically similar to the blood-brain barrier of the central nervous system. Because of this feature, the cochlea was originally considered an immunologically privileged organ. However, this postulate has been challenged by the evidence of an inflammatory response in the cochlea in the presence of bacterial or viral pathogens or antigens that can cause labyrinthitis. Although the main purpose of the inflammatory reaction is to protect against invading pathogens, the inflammatory response can also cause significant bystander injury to the delicate structures of the cochlea. The cochlear inflammatory response is characterised by the generation of proinflammatory mediators(cytokines, chemokines and adhesion molecules), and the recruitment of inflammatory cells(leukocytes). Here, we present an overview of the current research on cochlear inflammation, with particular emphasis on noise-induced cochlear inflammation. We also discuss treatment strategies aimed at the suppression of inflammation, which may potentially lead to mitigation of hearing loss.

Adenosine amine congener ameliorates cisplatin-induced hearing loss

AIM: To investigate a novel pharmacological intervention to mitigate cisplatin ototoxicity using a selective adenosine A1 receptor agonist adenosine amine congener(ADAC).METHODS: Male Wistar rats(8-10 wk) were exposed to a two-cycle cisplatin treatment similar to clinical course of cancer chemotherapy. Each cycle comprised 4 d of intraperitoneal cisplatin injections(1 mg/kg twice daily) separated by 10 d of rest. ADAC(100 μg/kg) or drug vehicle solution(control) was administered intraperitoneally for 5 d at 24 h intervals during the second cisplatin cycle(Regime 1), or upon completion of the cisplatin treatment(Regime 2). Hearing thresholds were measured using auditory brainstem responses(ABR) before cisplatin administration(baseline) and 7 d after the end of cisplatin treatment. Histological analysis of cochlear tissues included hair cell counting and qualitative assessment of apoptosis using terminal deoxynucleotidyl transferase mediated d UTP nick end labelling(TUNEL) staining.RESULTS: ABR threshold shifts in cisplatin-treated Wistar rats ranged from 5-29 d B across the frequency range used in the study(4-24 k Hz). Higher frequencies(16-24 k Hz) were mostly affected by cisplatin ototoxicity(mean threshold shift 25-29 d B). ADAC treatment during the second cisplatin cycle reduced cisplatininduced threshold shifts by 12-16 d B(P < 0.01) at higher frequencies compared to control vehicle-treated rats. However, the treatment was ineffective if ADAC administration was delayed until after the completion of the cisplatin regime. Functional recovery was supported by increased survival of hair cells in the cochlea. Qualitative analysis using TUNEL staining demonstrated reduced apoptosis of the outer hair cells and marginal cells in the stria vascularis in animals treated with ADAC during the second cisplatin cycle.CONCLUSION: A1 adenosine receptor agonist ADAC mitigates cisplatin-induced cochlear injury and hearing loss, however its potential interference with antineoplastic effects of cisplatin needs to be established.