Hearing loss is a major health concern in our society, affecting over 360 million people worldwide (World Health Organization, 2017). Aminoglycoside chemotherapy causes permanent hearing loss in 20-25% of treated patients. To date, no drugs have been approved by the Food and Drug Administration for protection from aminoglycoside-related hearing loss. Most candidate compounds currently in pre-clinical trials are related to antioxidants, vitamins, and glutathione metabolism, and thus many of these compounds, such as sodium thiosulfate, can interfere with aminoglycoside bactericidal activity. We have conducted a high-throughput screen of bioactive synthetic and natural compounds employing zebrafish as our platform for aminoglycoside ototoxicity and identified a natural compound as an important therapeutic molecule for aminoglycoside-induced cell death and hearing loss. Our Specific Aim is to test whether this natural compound protects from aminoglycoside-induced hearing loss by systemic delivery in a mouse model. Our approach is to intraperitoneally administer the compound for 15 days in adult C57BL/6 mice treated with kanamycin, measure their ABR and DPOAEs thresholds, EPs and analyze their cochlear histology. The maximum non-toxic dose of this compound will be experimentally determined and tested for hearing-protective effects. This work will shed light on the possibility of using this natural compound to combat aminoglycoside-induced hearing loss. The results of this study will provide the key proof of principle to develop novel therapeutic strategies against side effects of aminoglycoside chemotherapy. In the future, we will also test the efficacy of this compound to protect against cisplatin- noise- and age-related hearing loss. If successful, this proposal, has the potential to be a significant step forward for the treatment of aminoglycoside- induced hearing loss in patients suffering from severe Gram-negative bacterial infections.
Public Health Relevance Statement: PROJECT NARRATIVE The work in this proposal focuses on the development of a therapeutic natural product against aminoglycoside-induced hearing loss. If successful, this project will be a significant step forward in the treatment of aminoglycoside-induced hearing loss in patients with serious bacterial infections.
Project Terms: Adjuvant; Adult; Affect; Alkaloids; aminoglycoside-induced ototoxicity; Aminoglycosides; Animal Model; Animals; anti-cancer; Antibiotics; anticancer activity; Antidiabetic Drugs; Antifungal Agents; Antioxidants; Auditory Brainstem Responses; Auditory Threshold; auditory threshold shift; Bacterial Infections; bactericide; base; Blood - brain barrier anatomy; C57BL/6 Mouse; cancer therapy; Capsicum; Cell Death; cell injury; chemotherapy; Cisplatin; cisplatin induced hearing loss; Cochlea; combat; cytotoxicity; Development; Disease; Diuretics; Dose; drug candidate; efficacy testing; Embryo; Equilibrium; Fibroblasts; Future; Gentamicins; Glutathione Metabolism Pathway; Goals; Gram-Negative Bacterial Infections; Hair Cells; Health; Hearing; hearing impairment; Hearing Tests; high throughput screening; Histology; In Vitro; in vivo; in vivo Model; Infection; Inflammation; intraperitoneal; Jaborandi Pepper; Kanamycin; lateral line; Light; Measures; Morphology; mouse model; Mus; Natural Products; Neomycin; neuromast; Noise; novel therapeutics; Organ of Corti; otoacoustic emission; otoprotectant; Patients; permanent hearing loss; Pharmaceutical Preparations; Phase; pre-clinical; preclinical trial; Presbycusis; preservation; prevent; Prevention; Property; protective effect; Quinoxalines; side effect; small molecule libraries; Societies; sodium thiosulfate; spiral ganglion; Stria Vascularis; subcutaneous; Testing; Therapeutic; Time; Toxic effect; United States Food and Drug Administration; vitamin metabolism; Work; World Health Organization; Zebrafish
