Journal
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
Volume 40, Issue 1, Pages 175-181Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijmm.2017.3003
Keywords
pomegranate peel extract; oxidative stress; forkhead box O3a; ototoxicity
Categories
Funding
- Jinzhou Medical University Youth Science and Technology Staring Foundation Program [Y2012Z018]
- Liaoning Science and Technology Program [2014022029]
- Liaoning Education Program [L2015316]
- Undergraduate of Liaoning Province Innovation and Entrepreneurship Training Program [201410160023]
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The use of amikacin (AMK) in present treatment strategies results in severe ototoxicity; however, the underlying molecular mechanisms of this toxicity remain unclear. In this study, we investigated the effectiveness of orally administered pomegranate peel extract (PPE), a strong antioxidant, as a protective agent against AMK-induced ototoxicity. To this end, PPE was orally administered to adult BALB/c mice for 5 days, and the mice were then concurrently treated with AMK (500 mg/kg/day for 15 consecutive days). Auditory threshold shifts induced by AMK were significantly attenuated. The results of immunohistochemical staining and western blot analysis revealed that PPE exerted its protective effects by by downregulating the phosphorylation of Forkhead box O3a (FoxO3a), an important transcription factor which is involved in the responses to oxidative stress. The results also showed that PPE treatment inhibited mitogen-activated protein kinase phosphorylation, prevented the activation of pro-apoptotic protein caspase-3, decreased the levels of apoptosis-inducing Bax protein, and increased the levels of the anti-apoptotic mediator, Bcl-2, induced by AMK in the mouse cochlea. Taken together, our experimental findings suggest that phosphorylated FoxO3a mediates AMK-induced apoptosis in BALB/c mice cochlea. PPE effectively attenuated oxidative stress and ototoxicity by regulating FoxO3a, and may thus prove to be beneficial in protecting auditory cells from ototoxic drugs.
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