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Effects of Androgen Receptor Inhibition on Kanamycin-Induced Hearing Loss in Rats
Kyung-Ju Chun1, Chang-Ho Lee1, Kyung-Woon Kim1
1Department of Otorhinolaryngology-Head & Neck Surgery, CHA University College of Medicine, Seongnam 13496, Korea.
Abstract:
Megalin has been proposed as an endocytic receptor for aminoglycosides as well as estrogen and androgen. We aimed to investigate the otoprotective effects of antiandrogens (flutamide, FM) on kanamycin (KM)-induced hearing loss in rats. Rats were divided into four groups. The KM group was administered KM (20 mg/kg/day) for 5 days, while the FM group received FM (15 mg/kg/day) for 10 days. In the KM + FM group, KM and FM (15 mg/kg/day) were simultaneously injected for 5 days and then FM was injected for 5 days. Auditory brainstem responses were measured. Western blotting and/or quantitative reverse transcriptase-polymerase chain reaction were performed for megalin, cytochrome P450 1A1 (Cyp1a1), Cyp1b1, metallothionein 1A (MT1A), MT2A, tumor necrosis factor (TNF)-α, caspase 3, and cleaved caspase 3. The FM + KM group showed attenuated auditory thresholds when compared with the KM group at 4, 8, 16, and 32 kHz (all p < 0.05). The KM + FM group showed lower megalin and Cyp1b1 levels than the KM group (all p < 0.05). The KM + FM group revealed lower MT1A, TNFα, and caspase 3 protein levels, compared with those in the KM group (all p < 0.05). Androgen receptor inhibition protects against cochlear injuries in KM-induced hearing loss rats by attenuating megalin expression, revealing anti-inflammatory and anti-apoptotic effects.
Insights
Antiandrogen flutamide (FM) protects against kanamycin (KM)-induced hearing loss in rats. FM treatment reduced cochlear injury markers, suggesting otoprotective effects by inhibiting androgen receptor-mediated pathways.
Area of Science:
- Ototoxicology
- Pharmacology
- Molecular Biology
Background:
- Aminoglycosides like kanamycin (KM) can cause hearing loss.
- Megalin is implicated as an endocytic receptor for aminoglycosides and androgens.
- Antiandrogens may offer otoprotective benefits against drug-induced ototoxicity.
Purpose of the Study:
- To investigate the otoprotective effects of flutamide (FM) on kanamycin (KM)-induced hearing loss in a rat model.
- To explore the molecular mechanisms underlying FM's potential protective effects, focusing on megalin expression and inflammatory/apoptotic pathways.
Main Methods:
- Rats were administered KM and/or FM, with auditory brainstem responses measured.
- Western blotting and RT-PCR were used to analyze protein and gene expression levels.
- Key markers assessed included megalin, cytochrome P450 enzymes, metallothioneins, TNF-α, and caspase 3.
Main Results:
- FM treatment significantly attenuated auditory thresholds in KM-induced hearing loss rats.
- KM + FM group exhibited reduced levels of megalin and Cyp1b1 compared to the KM group.
- Lower protein levels of MT1A, TNF-α, and caspase 3 were observed in the KM + FM group.
Conclusions:
- Androgen receptor inhibition via flutamide protects against cochlear injury in kanamycin-induced hearing loss.
- Otoprotection is achieved by attenuating megalin expression and exhibiting anti-inflammatory and anti-apoptotic effects.
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