Unveiling the Role of Oxidative Stress in Cochlear Hair Cell Death: Prospective Phytochemical Therapeutics against Sensorineural Hearing Loss

Abstract

Hearing loss represents a multifaceted and pervasive challenge that deeply impacts various aspects of an individual's life, spanning psychological, emotional, social, and economic realms. Understanding the molecular underpinnings that orchestrate hearing loss remains paramount in the quest for effective therapeutic strategies. This review aims to expound upon the physiological, biochemical, and molecular aspects of hearing loss, with a specific focus on its correlation with diabetes. Within this context, phytochemicals have surfaced as prospective contenders in the pursuit of potential adjuvant therapies. These compounds exhibit noteworthy antioxidant and anti-inflammatory properties, which hold the potential to counteract the detrimental effects induced by oxidative stress and inflammation-prominent contributors to hearing impairment. Furthermore, this review offers an up-to-date exploration of the diverse molecular pathways modulated by these compounds. However, the dynamic landscape of their efficacy warrants recognition as an ongoing investigative topic, inherently contingent upon specific experimental models. Ultimately, to ascertain the genuine potential of phytochemicals as agents in hearing loss treatment, a comprehensive grasp of the molecular mechanisms at play, coupled with rigorous clinical investigations, stands as an imperative quest.

Keywords: apoptosis; cochlear hair cells; diabetes; hearing loss; inflammation; oxidative stress; phytochemical.

Figure 1

Molecular mechanisms underlying cochlear hair cell demise due to aging, noise exposure, or ototoxic medications: When cochlear hair cells are injured, the intrinsic and extrinsic apoptotic pathways are initiated, alongside the generation of ROS and disruptions to calcium balance. Damage to these cells triggers external inflammatory molecules like TNF-α to bind to their receptors on the cell membrane, initiating the cleavage and activation of procaspase 8. This sets off the extrinsic apoptotic cascade, activating effector caspases 3 and 7. Caspase 3 further triggers the degradation of anti-apoptotic Bcl-2 protein, releasing cytochrome c from mitochondria. It also activates CAD, leading to DNA fragmentation by cleaving its inhibitor ICAD. Typically, DNA repair is facilitated by PARPs, but caspases 3/7 inhibit this process, contributing to cellular degradation. Excessive DNA damage boosts the pro-apoptotic role of p53, upregulating genes like Bax and Bak. Furthermore, p53 directly interacts with Bak at the outer mitochondrial membrane, promoting cytochrome c release. Through the recruitment of procaspase 9 and Apaf-1, cytosolic cytochrome c assembles the apoptosome, which further activates caspases 3 and 7. Excessive ROS production surpassing antioxidant systems induces oxidative stress and DNA damage. Figure created with BioRender.com.

Figure 2

Cochlear insult: When cellular reactive oxygen species (ROS) are low, Nrf2 is degraded via proteasomal degradation facilitated by the Keap1 homodimer, which recruits the ubiquitin ligase Cul3 for subsequent ubiquitination. However, when cochlear hair cell injury occurs and ROS levels rise, Keap1 undergoes oxidation, leading to the accumulation of Nrf2 within the cytosol. This prompts Nrf2 to translocate into the nucleus, where it forms a complex with the leucine zipper-type transcription factor sMaf and binds to the antioxidant response element (ARE). This activation leads to the upregulation of antioxidant genes, counteracting the increased ROS levels in the cell. GSK3-β negatively regulates the Nrf2-dependent gene expression mechanism by phosphorylating Fyn, leading to its translocation into the nucleus, where it phosphorylates Nrf2. Phosphorylated Nrf2 is then exported from the nucleus back into the cytosol, inhibiting the antioxidant response. Additionally, GSK3-β activates the IKK complex and leads to the phosphorylation of IκB and its subsequent ubiquitination and degradation. The release of NF-κB and translocation to the nucleus promotes the transcription of proinflammatory cytokines that further worsens cell injury. The reduced antioxidant response, combined with the upregulation of proinflammatory cytokines, makes the cell more susceptible to apoptosis. Phytochemical therapy involving substances like rosmarinic acid, Ginkgo biloba, and curcumin enhances the cellular response to increased ROS levels. Ginkgo biloba and curcumin activate Akt, inhibiting the GSK3-β-induced phosphorylation cascade. Without Fyn stimulating Nrf2 nuclear exclusion, Nrf2 can activate the antioxidant program, helping to scavenge ROS. Although various phytochemicals are known to stimulate Nrf2 and the transcription of its downstream antioxidant genes, specific mechanisms are still being investigated. Nevertheless, administering these phytochemicals effectively combats oxidative stress, promoting the survival and function of cochlear hair cells. Figure created with BioRender.com.

Figure 3

Molecular mechanisms mediating the potential protective effects of phytochemicals against SNHL: The effectiveness of phytochemicals has been evaluated across various models of SNHL with particular emphasis on cisplatin ototoxicity. Across these models, phytochemicals demonstrate a protective effect against cochlear damage primarily by regulating oxidative stress and inflammatory pathways. Additionally, phytochemicals such as resveratrol and curcumin provide protection by activating SIRT and STAT signaling pathways, respectively. Further research is warranted to elucidate additional specific targets mediating the effects of phytochemicals in the cochlea. Figure created with BioRender.com.