Adjudin Protects Rodent Cochlear Hair Cells Against Gentamicin Ototoxicity Via the SIRT3-ROS Pathway

Overview

Journal Sci Rep

Specialty Science

Date 2015 Feb 3

PMID 25640330

Citations 45

Authors

Yizhou Quan

Li Xia

Jiaxiang Shao

Shankai Yin

C Yan Cheng

Weiliang Xia

Wei-Qiang Gao

Affiliations

Soon will be listed here.

Abstract

Hearing loss resulting from hair cell degeneration is a common disease that affects millions of people worldwide. Strategies to overcome the apparent irreversible hair cell loss in mammals become paramount for hearing protection. Here we reported that, by using a well-established gentamicin-induced hair cell loss model in vitro, adjudin, a multi-functional small molecule drug, protected cochlear hair cells from gentamicin damage. Immunohistochemistry, Western blotting and quantitative RT-PCR analyses revealed that adjudin exerted its otoprotective effects by up-regulating the level of Sirt3, a member of Sirtuin family protein located in mitochondria, which regulates reactive oxygen species (ROS) production in cochlear cells and inhibits the production of ROS and apoptotic cells induced by gentamicin. Sirt3 silencing experiments confirmed that Sirt3-ROS signaling axis mediated hair cell protection against gentamicin by adjudin, at least in part. Furthermore, adjudin's otoprotection effects were also observed in an in vivo gentamicin-injured animal model. Taken together, these findings identify adjudin as a novel otoprotective small molecule via elevating Sirt3 levels and Sirt3 may be of therapeutic value in hair cell protection from ototoxic insults.

Citing Articles

Hearing loss during chemotherapy: prevalence, mechanisms, and protection.

Kessler L, Koo C, Richter C, Tan X Am J Cancer Res. 2024; 14(9):4597-4632.

PMID: 39417180 PMC: 11477841. DOI: 10.62347/OKGQ4382.

Ototoxic Effect of Nicotinamide Riboside.

Ivanov S, Podyacheva E, Zhuravskii S, Toropova Y Bull Exp Biol Med. 2024; 177(5):639-642.

PMID: 39340621 DOI: 10.1007/s10517-024-06240-7.

Roles of Sirtuins in Hearing Protection.

Koo C, Richter C, Tan X Pharmaceuticals (Basel). 2024; 17(8).

PMID: 39204103 PMC: 11357115. DOI: 10.3390/ph17080998.

Sirtuin insights: bridging the gap between cellular processes and therapeutic applications.

Kamal S, Babar S, Ali W, Rehman K, Hussain A, Akash M Naunyn Schmiedebergs Arch Pharmacol. 2024; 397(12):9315-9344.

PMID: 38976046 DOI: 10.1007/s00210-024-03263-9.

Sirtuins and Cellular Senescence in Patients with Idiopathic Pulmonary Fibrosis and Systemic Autoimmune Disorders.

DAgnano V, Mariniello D, Pagliaro R, Far M, Schiattarella A, Scialo F Drugs. 2024; 84(5):491-501.

PMID: 38630364 PMC: 11189987. DOI: 10.1007/s40265-024-02021-8.

References

Sano H, Yoneda S, Iwase H, Itoh A, Hashimoto D, Okamoto M . Effect of geranylgeranylacetone on gentamycin ototoxicity in rat cochlea culture. Auris Nasus Larynx. 2006; 34(1):1-4. DOI: 10.1016/j.anl.2006.05.020. View

Okano T, Kelley M . Stem cell therapy for the inner ear: recent advances and future directions. Trends Amplif. 2012; 16(1):4-18. PMC: 4040847. DOI: 10.1177/1084713812440336. View

Kim H, Patel K, Muldoon-Jacobs K, Bisht K, Aykin-Burns N, Pennington J . SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010; 17(1):41-52. PMC: 3711519. DOI: 10.1016/j.ccr.2009.11.023. View

Fan J, Cai H, Tan W . Role of the plasma membrane ROS-generating NADPH oxidase in CD34+ progenitor cells preservation by hypoxia. J Biotechnol. 2007; 130(4):455-62. DOI: 10.1016/j.jbiotec.2007.05.023. View

Tabuchi K, Pak K, Chavez E, Ryan A . Role of inhibitor of apoptosis protein in gentamicin-induced cochlear hair cell damage. Neuroscience. 2007; 149(1):213-22. DOI: 10.1016/j.neuroscience.2007.06.061. View

Kim S, Shin B, Choi I, Kim D, Kim M, Myung N . Hwanggunchungyitang prevents cadmium-induced ototoxicity through suppression of the activation of caspase-9 and extracellular signal-related kinase in auditory HEI-OC1 cells. Biol Pharm Bull. 2009; 32(2):213-9. DOI: 10.1248/bpb.32.213. View

Choung Y, Taura A, Pak K, Choi S, Masuda M, Ryan A . Generation of highly-reactive oxygen species is closely related to hair cell damage in rat organ of Corti treated with gentamicin. Neuroscience. 2009; 161(1):214-26. PMC: 2730735. DOI: 10.1016/j.neuroscience.2009.02.085. View

Schacht J, Talaska A, Rybak L . Cisplatin and aminoglycoside antibiotics: hearing loss and its prevention. Anat Rec (Hoboken). 2012; 295(11):1837-50. PMC: 3596108. DOI: 10.1002/ar.22578. View

Shao J, Liu T, Xie Q, Zhang T, Yu H, Wang B . Adjudin attenuates lipopolysaccharide (LPS)- and ischemia-induced microglial activation. J Neuroimmunol. 2012; 254(1-2):83-90. PMC: 4108195. DOI: 10.1016/j.jneuroim.2012.09.012. View

10.

Mizutari K, Fujioka M, Hosoya M, Bramhall N, Okano H, Okano H . Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron. 2013; 77(1):58-69. PMC: 3573859. DOI: 10.1016/j.neuron.2012.10.032. View

11.

Rubel E, Furrer S, Stone J . A brief history of hair cell regeneration research and speculations on the future. Hear Res. 2013; 297:42-51. PMC: 3657556. DOI: 10.1016/j.heares.2012.12.014. View

12.

Lee J, Park C, Kim S, Kim H, Oh G, Shen A . Different uptake of gentamicin through TRPV1 and TRPV4 channels determines cochlear hair cell vulnerability. Exp Mol Med. 2013; 45:e12. PMC: 3641395. DOI: 10.1038/emm.2013.25. View

13.

Zheng J, Gao W . Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nat Neurosci. 2000; 3(6):580-6. DOI: 10.1038/75753. View

14.

Cheng C, Silvestrini B, Grima J, Mo M, Zhu L, Johansson E . Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis. Biol Reprod. 2001; 65(2):449-61. DOI: 10.1095/biolreprod65.2.449. View

15.

Ylikoski J, Virkkala J, Pirvola U . Blockade of c-Jun N-terminal kinase pathway attenuates gentamicin-induced cochlear and vestibular hair cell death. Hear Res. 2002; 166(1-2):33-43. DOI: 10.1016/s0378-5955(01)00388-4. View

16.

Setsukinai K, Urano Y, Kakinuma K, Majima H, Nagano T . Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species. J Biol Chem. 2002; 278(5):3170-5. DOI: 10.1074/jbc.M209264200. View

17.

Salt A, Kellner C, Hale S . Contamination of perilymph sampled from the basal cochlear turn with cerebrospinal fluid. Hear Res. 2003; 182(1-2):24-33. DOI: 10.1016/s0378-5955(03)00137-0. View

18.

Wang J, Van De Water T, Bonny C, de Ribaupierre F, Puel J, Zine A . A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J Neurosci. 2003; 23(24):8596-607. PMC: 6740364. View

19.

McFadden S, Ding D, Jiang H, Salvi R . Time course of efferent fiber and spiral ganglion cell degeneration following complete hair cell loss in the chinchilla. Brain Res. 2004; 997(1):40-51. DOI: 10.1016/j.brainres.2003.10.031. View

20.

Floridi A, Paggi M, DAtri S, De Martino C, Marcante M, Silvestrini B . Effect of lonidamine on the energy metabolism of Ehrlich ascites tumor cells. Cancer Res. 1981; 41(11 Pt 1):4661-6. View