Drug-Therapeutic Strategies for Noise-Induced Hearing Loss: A Narrative Review

Abstract

With the rapid development of industrialisation, noise exposure is becoming increasingly prevalent. The detrimental effects of noise-induced hearing loss (NIHL) have become clinically relevant. Therefore, effective drug therapeutic strategies for NIHL are urgently needed. This article reviewed the pathophysiology and potential molecular mechanisms of NIHL and classified and summarised the drug therapeutic strategies. Drug therapeutic strategies of NIHL can be further studied in agents such as corticosteroids, antioxidants, neurotrophic factors, herbal medicine, magnesium and statins. Given the current research progress, ongoing positive test results and pilot studies may lead to new pharmacological regimens to alleviate NIHL.

KEY MESSAGES

• (1)Noise-induced hearing loss (NIHL) is caused by hair cell damage through mechanisms such as oxidative stress, calcium overload and apoptosis signalling pathways.
• (2)Various pharmacologic agents, such as corticosteroids, antioxidants, neurotrophic factors and herbal medicine, have been confirmed to play a protective role in NIHL.
• (3)Further mechanistic studies and clinical trials are needed to develop new drug-therapeutic strategies for NIHL.

INTRODUCTION

Noise-induced hearing loss (NIHL) is a progressive auditory disorder caused by long-term exposure to external noise. With the progress of national economy and the development of industrialisation, the issues and detrimental effects of noise pollution are becoming increasingly prominent. At present, noise pollution is considered one of the top 10 public hazards in the world, which seriously affects human health.[1] Studies have found that prolonged exposure to noise is correlated with diminished learning and cognitive abilities compared with individuals not subjected to such noise, and the consensus is that the resultant damage is an irreversible change.[2,3] In recent years, research on the pathogenesis of NIHL has advanced, encompassing mechanical damage, metabolic damage and vascular changes.[4] However, targeted treatment remains in the exploratory stage, and the treatment efficacy is uncertain, presenting a major challenge for global drug development. Current literature showed that pharmacological treatment could alleviate NIHL to some extent.[5] Therefore, this article reviews the research progress of pathophysiology and drug therapeutic strategies for NIHL in recent years.

PATHOPHYSIOLOGY OF NIHL

Types of NIHL

The current consensus is that NIHL can cause the following two types of inner ear damage: temporary threshold shift (TTS) and permanent threshold shift (PTS).[6] TTS generally recovers within 2 days, but it can accelerate age-related hearing loss; therefore, recreational noise exposure in contemporary people may exacerbate age-related hearing loss and reduce future quality of life.[7] PTS is usually not readily apparent, as its audiogram characteristics often fall in the range of 3–6 kHz. Minor NIHL generally leads to difficulties in distinguishing between speech and background noise. Severe NIHL may affect speech perception and expand the damage until patients reach complete deafness.[8]

Pathophysiology of NIHL

As the most complex organ of the human body, the inner ear relates people with the outside world through the sense of hearing. The inner and outer hair cells in the cochlear organs can transduce sound into nerve pulses. In both types of hair cells, the inner hair cells are often considered the main sensors, mostly innervated by afferent and efferent nerves to enhance the sensitivity of sound stimulation.[9] When only outer hair cells are absent, the hearing threshold increases by 40 dB, and damaged inner hair cells lead to an elevated hearing threshold, which causes complete deafness.[10]

Acoustic trauma induces cochlear outer hair cell loss, fusion of inner hair cell stereocilia and histological changes in the cochlea, leading to permanent hearing loss.[11] Although NIHL is generally associated with symmetric mild to moderate hearing loss and tinnitus, studies reveal significant variability. Many patients exhibit asymmetric hearing thresholds and diverse noise exposure histories, with some progressing to severe hearing impairment.[12]

A systematic review of occupational noise exposure showed that noise-affected workers experience worse hearing impairment than non-noise-affected workers, and the risk of hearing loss increases with age.[13] In these populations, the change in cochlear outer hair cell loss is the most pronounced, whereas the loss of inner hair cells remains within a certain range. Injury to the outer hair cells in the cochlea is associated with the degeneration of nerve fibres. Increased noise exposure can exacerbate this condition, potentially resulting in comprehensive cochlear damage, which is typically irreversible.[14]

The escalating burden of NIHL pathogenesis highlights the urgent need for targeted pharmacological interventions. Despite the availability of many pharmaceutical agents (e.g., steroids, antioxidants and neurotrophins), restoring hearing function to the original state after hearing damage remains challenging due to the lack of spontaneous regeneration of hair cells and spiral neurons.

MECHANISMS OF HAIR CELL DAMAGE

Environmental factors

Hearing loss in some populations may be caused by long-term exposure to noise, termed NIHL, whereas hearing loss can also occur due to one or more instances of sudden noise exposure, commonly referred to as auditory trauma. Exposure to a sudden pulse noise environment is more harmful than exposure to a steady-state noise environment.[15] TTS can recover within 2 days, but the ribbon synapses may sustain persistent damage. The rapid degeneration of synapses is called synaptosis, also referred to as noise-induced recessive hearing loss. Some scholars argue that these synaptoses may be involved in NIHL.[16] In PTS, damage to the Corti organ may result from the following two mechanisms: mechanical damage caused by short-term exposure to noise and metabolic disorders caused by prolonged exposure to noise. The average hearing threshold increases significantly when subjected to noise levels over 120–130 dB, leading to mechanical damage.[17]

Inherent factors

Animal models have demonstrated genetic susceptibility to NIHL, with otoferlin gene mutations identified as the primary cause of hearing impairment and deafness in auditory neuropathy.[18] A study showed that mice with genetic defects in these genes possess an incomplete cochlear structure and exhibit heightened sensitivity to noise-induced damage.[19] Single nucleotide polymorphism is a common mutation site in the genome associated with NIHL, playing functional roles in the inner ear and its genotyping is considered a successful tool for analysing the genetic basis of NIHL.[19] Multiple mutations in these genes (e.g., GJB 2, GJB 3 and GJB 6) can lead to NIHL.[20,21]

Oxidative stress and mitochondrial dysfunction

The present theoretical mechanisms of metabolic damage mainly focus on the formation of free radicals or reactive oxygen species (ROS) and glutamate excitotoxicity caused by excessive noise, which subsequently promotes the activation of apoptosis signalling pathways.[22] Currently, mitochondrial dysfunction has been recognised as the primary mechanism of NIHL, and it is also involved in other acquired hearing diseases. The mitochondrial electron transport chain is considered the main source of ROS in all tissues. Under normal physiological conditions, 1% of oxygen molecules may be reduced to superoxide, which can be converted by mitochondrial superoxide dismutase into less toxic hydrogen peroxide or generate more harmful compounds, such as hydroxyl radicals.

NIHL can increase the production of ROS in the cochlear tissue, alongside other free radicals in the form of reactive nitrogen species derived from NO, both of which can inflict damage on cochlear tissue.[23] ROS can diffuse from the basal end of the organ of Corti towards the apex and persist for over a week. ROS can cause apoptosis of cochlear hair cells, culminating in irreversible hearing impairment.[24] In a high-noise environment, inadequate capillary blood flow fails to supply sufficient oxygen and nutrients to maintain the ion gradient across the cell membrane, leading to localised vascular constriction, which may disrupt cellular energy metabolism and cause temporary or permanent NIHL.[25]

Administering creatine as an energy source was found to sustain cochlear adenosine triphosphate (ATP) levels and alleviate NIHL. Creatine kinase serves as a source of ATP, which is prevalent in the vascular structure; thus, creatine can provide ATP via the ion pump to maintain the ionic equilibrium in the cochlear tissue, protecting the hair cells in the cochlea.[26] Creatine can reduce the ROS content in mitochondria, alleviating NIHL. Simultaneously, adenosine monophosphate (AMP) activated protein kinase (AMPK) functions as a self-regulating energy sensor, capable of modulating the variations in the AMP/ATP ratio by inhibiting energy consumption activity or activating the energy generation pathway.[27] Activation of the AMPK pathway can upregulate the expression of the proapoptotic factor Bim, which then activates the apoptosis-related pathway in NIHL and accelerates the accumulation of ROS within the mitochondria.[28] Therefore, inhibiting activation of the AMPK pathway by specific pharmaceutical agents or inhibitors (e.g., dormorphine) alleviates NIHL and cochlear synapsis.

Calcium overload

Another important mechanism of NIHL is that excessive noise exposure leads to a sharp rise in the concentrations of free calcium ion (Ca²⁺) in the outer hair cells, and calcium overload can induce cell apoptosis and necrosis.[29] One study found that low-calcium levels may contribute in preventing NIHL.[30] Furthermore, calcium overload can trigger any type of apoptosis by activating certain calcium-dependent pathways. Immunohistochemical results indicate that calcium overload can cause synaptopathy by stimulating the excessive release of glutamate neurotransmitters. The overactivation of glutamate receptors in postsynaptic nerve terminals will enhance excitotoxicity and swelling of nerve endings, resulting in functional defects of cochlear organs.[31,32] The utilisation of calcium channel blockers (CCBs) can alleviate NIHL, confirming the involvement of calcium channels in auditory damage caused by noise. In a noise-exposure environment, several CCBs (e.g., verapamil, diltiazem and nimodipine) in the Ca²⁺ channels in inner and outer hair cells can effectively alleviate hair cell damage and hearing loss caused by noise exposure in animals.[33]

Apoptosis signalling pathway of cochlear hair cells

Noise-induced hair cell apoptosis usually involves two complex signalling pathways, namely, endogenous and exogenous cell apoptosis signalling. In situations with strong noise exposure, extracellular stimuli initiate an exogenous cell apoptosis signalling pathway by inducing transmembrane apoptosis receptors. These receptors activate caspase-8, which triggers downstream signalling pathways and facilitates apoptosis in cochlear hair cells.[34,35,36] The endogenous cell apoptosis pathway, triggered by changes in mitochondrial membrane permeability, stimulates caspase-9 and releases cytochrome c from mitochondria, resulting in programmed cell death. Together with caspase, the receptor-interacting protein kinase participates in the activation of apoptosis-related pathways in hair cells. Other studies have shown that c-Jun N-terminal kinase (JNK) signalling can also activate the mitochondrial apoptotic pathway after noise trauma.[37,38] The caspase-independent apoptosis pathway is also involved in the noise-mediated hair cell damage process. After exposure to high noise intensity, mitochondria release apoptosis-inducing factors (AIFs) and endonuclease G (EndoG) via the mitochondrial outer membrane. EndoG nuclear transfer initiates apoptosis, whereas AIFs, although not directly involved in apoptosis, exacerbate oxidative stress damage during noise-induced oxidative stress damage.[39]

Animal models of NIHL

Animal models of NIHL are essential tools used to understand the molecular mechanisms underlying NIHL and can assist researchers in identifying key therapeutic targets and novel therapeutic agents. These NIHL animal models include mammals, non-mammalian, vertebrates and invertebrates.

Mechanism-driven therapies for rodents with NIHL

Long-tailed chinchillas have human-like hearing with a hearing frequency range from 50 Hz to 33 kHz, so they are frequently used as a model for investigating hearing impairment resulting from exposure to acute, chronic or intermittent noise. The pharmacological effects of antioxidants (d-methionine, N-acetylcysteine [NAC] or acetyl-L-carnitine) and JNK inhibitor (AM-111) have been demonstrated in the treatment of NIHL in long-tailed chinchillas, exhibiting a decelerating effect.[40] Guinea pigs, with similar auditory characteristics to long-tailed chinchillas, also demonstrate similarities to human hearing, with a hearing frequency range from 50 Hz to 50 kHz. Experimental animal studies have shown that neuromodulators (e.g., N-methyl-D-aspartic acid), JNK and caspase inhibitors, anti-inflammatory molecules (glucocorticoids), antioxidants and nutritional factors can effectively alleviate NIHL.[41]

Mechanism-driven therapies for non-rodents with NIHL

Non-rodent species such as fishes and birds can enhance our understanding of hearing loss. Zebrafish can offer genetic tractability and suitability for drug screening. Current studies on zebrafish have found many high-throughput pharmaceutical agents to alleviate NIHL.[42] Non-human primates are a key experimental model for medical development during the final stages of preclinical research because of their phylogenetic similarity to humans. One study found that the discrepancy in hearing loss expression between rodents and primates may account for the phenotypic difference. The limitations of rodent models can be circumvented by using non-human primate models.[43]

PHARMACOLOGIC AGENTS FOR NIHL

Corticosteroids

Studies have found that different types of corticosteroids can reduce NIHL, especially when delivered before noise exposure or following an endolymphatic injection. The anti-inflammatory properties of corticosteroids can significantly mitigate NIHL. Various routes of administration, such as tympanic injection, intraperitoneal injections or direct inner ear injection, have demonstrated clear therapeutic and protective effects.[44,45] Clinical studies provide evidence that corticosteroids offer protection against acute NIHL. However, long-term steroid use has several adverse effects.[46,47] Therefore, corticosteroids are not the optimal choice for addressing long-term occupational noise exposure. The pharmacologically agents and typical drugs are shown in [Table 1].

Table 1.

Summary of pharmacologic agents for NIHL

Pharmacologic agents	Typical drugs	Mechanism
Corticosteroids	Dexamethasone, prednisone, prednisolone, methylprednisolone	Immune suppression, anti-inflammatory functions
Antioxidants	Glutathione, D-methionine, resveratrol, ascorbate, water-soluble coenzyme Q10	Counteract oxidative stress, regulate intracellular redox homeostasis, reduce ROS
Neurotrophic factors	Neurotrophin-3, glial cell-derived neurotrophic factor	Recovery of the number and function of ribbon synapses
Herbal medicine	Polygonum multiflorum Thunb., Panax ginseng C.A. Mey, Pueraria lobata (Willd.) Ohwi., Ginaton	Anti-oxidative, neuroprotective, anti-inflammatory, anti-apoptotic, mitochondrial protective effects
Other pharmacological agents	Magnesium, statins	Reduce oxidative stress, improve hair cell survival

Note: NIHL, noise-induced hearing loss; ROS, reactive oxygen species.

Antioxidants

Antioxidants, as alternatives to corticosteroids, have few side effects. Free oxygen radicals and oxidative stress are crucial in the pathogenesis of NIHL. Therefore, antioxidants may serve as an effective treatment.[48] Antioxidants such as glutathione (GSH),[49,50,51] D-methionine,[52] resveratrol,[53] ascorbate[54] and water-soluble coenzyme Q10[55] have demonstrated efficacy in alleviating NIHL to some extent.

N-acetyl cysteine (NAC), as a precursor of GSH, is essential for maintaining intracellular antioxidant levels. Research has found that NAC can protect the cochlea in noise-exposed environments.[56] However, its clinical efficacy remains controversial.[57] One study demonstrated that oral administration of NAC (1.2 g/day for 14 days) can remarkably improve TTS, but a dosage of 900 mg/day NAC does not provide significant protection for the cochlea.[58] In one study, 24 male albino Wistar rats were randomly allocated into following four groups: one control group and three treatment groups. Group A received 1250 mg/kg/day ascorbic acid, Group B received 250 mg/kg/day ascorbic acid, Group C received 50 mg/kg/day ascorbic acid and Group D acted as the control group. The results showed that Groups A and B significantly reduced the transient threshold shift in the rats.[59] Additionally, red ginseng and Vitamin B₁₂ have been reported to alleviate NIHL, although the results remain controversial.[60,61] Despite the limited protective effects of these antioxidants in alleviating NIHL, the use of antioxidants to reduce oxidative stress remains a priority in current research.

Neurotrophic factors

Studies have shown that neurotrophin-3 (NT-3) and brain derived neurotrophic factor are crucial for the formation and maintenance of ribbon synapses in the cochlea, and NT-3 plays important roles in promoting the recovery of these synapses.[62,63] A study found that the prolonged administration of glial cell-derived neurotrophic factor (GDNF) via direct injection into the guinea pig cochlea exhibits a dose-dependent effect on the preservation of cochlear cells and the reduction of hearing threshold.[64] The effect of GDNF have the potential to cure neurodegenerative diseases.[65]

Herbal medicine

In recent years, many effective ingredients from Chinese herbal medicine and other plants have been identified and extensively researched, among which triterpenoids, flavonoids and phenolic compounds have gradually assumed the role of antioxidant pharmaceutical agents for the treatment of NIHL.[66] For example, Renexin, a compound of cilostazol and ginkgo biloba extract, can protect the cochlear efferent nervous system and effectively alleviate NIHL.[67] Some scholars have found that ginkgo extract offers protection against NIHL and its secondary comorbidities, such as tinnitus.[68,69] Curcumin can attenuate H₂O₂-induced apoptosis and cell senescence in auditory hair cells and prevent mitochondrial function dysfunction, making it a promising therapeutic candidate for the prevention of NIHL.[70]

Other pharmacologic agents

Blocking the calcium overload-induced cell apoptosis pathway has proven to be another successful approach in preventing NIHL. Blocking calcium channels was found to be protective against NIHL in mice, and the calcineurin inhibitor FK506 has consistent protective effects in calcium-mediated hair cell injury in the cochlea.[71] Other pharmacologic agents that confer protection against NIHL include magnesium and statins, which have been validated in humans and animal models [Table 1]. An increase in the magnesium ion concentration can reduce calcium influx to inhibit apoptosis, reduce ROS formation, induce vasodilation in cochlear arterioles to limit ischemia and decrease the damage of cochlear hair cells.[72] One study has also found that statins can improve hair cell survival by reducing oxidative stress, dramatically alleviating NIHL.[73]

CONCLUSION

The detrimental effects of noise on auditory perception occur gradually, making early detection and treatment highly significant. In the past decade, remarkable progress has been made in the prevention and treatment of NIHL. Various pharmacological agents, such as corticosteroids, antioxidants, neurotrophic factors, magnesium and statins, have been confirmed to play a protective role in NIHL. However, the application of these drugs to alleviate NIHL primarily focuses on animal models, and their effects remain controversial and limited for humans.

Research on mechanism-driven therapies to alleviate NIHL in China is still in its infancy, so significant progress is required in drug therapeutic strategies for NIHL. Further mechanistic studies and clinical trials are needed to develop new drug therapeutic strategies.

Author Contributions

Zehui Deng is responsible for writing the article and organizing the materials; Lin Fei is in charge of the article’s structure, revising the article, and contacting for submission; Ling Zhou, Shaojuan Wang, Jie Li, and Longxi He are responsible for collecting materials and providing feedback on the article.

Availability of Data and Materials

The datasets used and/or analysed in this article are available from the corresponding author.

Conflicts of Interest

There are no conflicts of interest.

Funding Statement

Nil.