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Aminoglycoside ototoxicity in three murine strains and effects on NKCC1 of stria vascularis
Han-qi Chu1, Hao Xiong, Xiao-qin Zhou
1Department of Otolaryngology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. qi7chu@163.com
Background:
After establishing a murine model of aminoglycoside antibiotic (AmAn) induced ototoxicity, the sensitivity of AmAn induced ototoxicity in three murine strains and the effect of kanamycin on the expression of Na-K-2Cl cotransporter-1 (NKCC1) in stria vascularis were investigated.
Methods:
C57BL/6J, CBA/CaJ, NKCC1(+/-) mice (24 of each strain) were randomly divided into four experimental groups: A: kanamycin alone; B: kanamycin plus 2, 3-dihydroxybenzoate; C: 2, 3-dihydroxybenzoate alone; and D: control group. Mice were injected with kanamycin or/and 2, 3-dihydroxybenzoate twice daily for 14 days. Auditory brainstem response (ABR) was measured and morphology of cochlea delineated with succinate dehydrogenase staining. Expression of NKCC1 in stria vascularis was detected immunohistochemically.
Results:
All three strains in groups A and B developed significant ABR threshold shifts (P < 0.01), which were accompanied by outer hair cell loss. NKCC1 expression in stria vascularis was the weakest in group A (A cf D, P < 0.01) and the strongest in groups C and D (P < 0.05). CBA/CaJ mice had the highest sensitivity to AmAn.
Conclusions:
Administration of kanamycin established AmAn induced ototoxicity. Kanamycin inhibited the expression of NKCC1 in stria vascularis. 2, 3-dihydroxybenzoate attenuated AmAn induced ototoxicity-possibly by enhancing the expression of NKCC1. Age related hearing loss did not show additional sensitivity to AmAn induced ototoxicity in murine model.
Insights
Aminoglycoside antibiotics cause ototoxicity, damaging hearing by reducing Na-K-2Cl cotransporter-1 (NKCC1) expression. 2,3-dihydroxybenzoate may protect hearing by enhancing NKCC1 levels.
Area of Science:
- Ototoxicity research
- Auditory neuroscience
- Pharmacology
Background:
- Aminoglycoside antibiotics (AmAn) can induce ototoxicity, a significant concern in clinical practice.
- Investigating the ototoxic effects of AmAn in different mouse strains and their impact on specific molecular pathways is crucial.
Purpose of the Study:
- To establish a murine model of AmAn-induced ototoxicity.
- To assess the sensitivity of different murine strains to AmAn ototoxicity.
- To determine the effect of kanamycin on Na-K-2Cl cotransporter-1 (NKCC1) expression in the stria vascularis.
Main Methods:
- Three mouse strains (C57BL/6J, CBA/CaJ, NKCC1(+/-)) were used, with groups receiving kanamycin alone, kanamycin plus 2,3-dihydroxybenzoate, 2,3-dihydroxybenzoate alone, or control.
- Auditory brainstem response (ABR) and cochlear morphology were assessed after 14 days of treatment.
- Immunohistochemistry was employed to detect NKCC1 expression in the stria vascularis.
Main Results:
- Kanamycin administration induced significant ABR threshold shifts and outer hair cell loss in all tested strains.
- NKCC1 expression in the stria vascularis was significantly reduced by kanamycin treatment.
- CBA/CaJ mice exhibited the highest sensitivity to AmAn-induced ototoxicity.
Conclusions:
- Kanamycin effectively induced ototoxicity in the established murine model.
- Kanamycin administration inhibited NKCC1 expression, suggesting a role in ototoxicity.
- 2,3-dihydroxybenzoate demonstrated a potential protective effect against AmAn-induced ototoxicity, possibly by upregulating NKCC1.
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