Rescue of Hearing, Auditory Hair Cells, and Neurons by CEP-1347/KT7515, an Inhibitor of C-Jun N-terminal Kinase Activation

Overview

Journal J Neurosci

Specialty Neurology

Date 2000 Jan 11

PMID 10627579

Citations 107

Authors

U Pirvola

J Virkkala

M Saarma

C Murakata

A M Camoratto

K M Walton

J Ylikoski

Affiliations

Soon will be listed here.

Abstract

We have studied the mechanisms of auditory hair cell death after insults in vitro and in vivo. We show DNA fragmentation of hair cell nuclei after ototoxic drug and intense noise trauma. By using phospho-specific c-Jun-N-terminal kinase (JNK) and c-Jun antibodies in immunohistochemistry, we show that the JNK pathway, associated with stress, injury, and apoptosis, is activated in hair cells after trauma. CEP-1347, a derivative of the indolocarbazole K252a, is a small molecule that has been shown to attenuate neurodegeneration by blocking the activation of JNK (). Subcutaneously delivered CEP-1347 attenuated noise-induced hearing loss. The protective effect was demonstrated by functional tests, which showed less hearing threshold shift in CEP-1347-treated than in nontreated guinea pigs, and by morphometric methods showing less hair cell death in CEP-1347-treated cochleas. In organotypic cochlear cultures, CEP-1347 prevented neomycin-induced hair cell death. In addition to hair cells, CEP-1347 promoted survival of dissociated cochlear neurons. These results suggest that therapeutic intervention in the JNK signaling cascade, possibly by using CEP-1347, may offer opportunities to treat inner ear injuries.

Citing Articles

Pan-caspase inhibitor protects against noise-induced hearing loss in a rodent model.

Yepes M, Minesinger K, Raciti F, Salazar M, Rajguru S Front Neurosci. 2025; 19:1497773.

PMID: 39995440 PMC: 11847858. DOI: 10.3389/fnins.2025.1497773.

Exploring the bioactive ingredients of three traditional Chinese medicine formulas against age-related hearing loss through network pharmacology and experimental validation.

Shi W, Zhao Q, Gao H, Yang Y, Tan Z, Li N Naunyn Schmiedebergs Arch Pharmacol. 2024; .

PMID: 39356317 DOI: 10.1007/s00210-024-03464-2.

Pathogenesis and New Pharmacological Approaches to Noise-Induced Hearing Loss: A Systematic Review.

Santaolalla Sanchez F, Gutierrez Posso J, Santaolalla Montoya F, Zabala J, Arrizabalaga-Iriondo A, Revuelta M Antioxidants (Basel). 2024; 13(9).

PMID: 39334764 PMC: 11428627. DOI: 10.3390/antiox13091105.

Redox homeostasis dysregulation in noise-induced hearing loss: oxidative stress and antioxidant treatment.

Zhou Y, Fang C, Yuan L, Guo M, Xu X, Shao A J Otolaryngol Head Neck Surg. 2023; 52(1):78.

PMID: 38082455 PMC: 10714662. DOI: 10.1186/s40463-023-00686-x.

Aminoglycosides-Related Ototoxicity: Mechanisms, Risk Factors, and Prevention in Pediatric Patients.

Rivetti S, Romano A, Mastrangelo S, Attina G, Maurizi P, Ruggiero A Pharmaceuticals (Basel). 2023; 16(10).

PMID: 37895824 PMC: 10610175. DOI: 10.3390/ph16101353.

References

Behrens A, Sibilia M, Wagner E . Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet. 1999; 21(3):326-9. DOI: 10.1038/6854. View

Mizukami Y, Yoshioka K, Morimoto S, Yoshida K . A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion. J Biol Chem. 1997; 272(26):16657-62. DOI: 10.1074/jbc.272.26.16657. View

Nakagawa T, Yamane H, Takayama M, Sunami K, Nakai Y . Apoptosis of guinea pig cochlear hair cells following chronic aminoglycoside treatment. Eur Arch Otorhinolaryngol. 1998; 255(3):127-31. DOI: 10.1007/s004050050027. View

Hirose K, Hockenbery D, Rubel E . Reactive oxygen species in chick hair cells after gentamicin exposure in vitro. Hear Res. 1997; 104(1-2):1-14. DOI: 10.1016/s0378-5955(96)00169-4. View

Glicksman M, Chiu A, Dionne C, Harty M, Kaneko M, Murakata C . CEP-1347/KT7515 prevents motor neuronal programmed cell death and injury-induced dedifferentiation in vivo. J Neurobiol. 1998; 35(4):361-70. View

Priuska E, Schacht J . Formation of free radicals by gentamicin and iron and evidence for an iron/gentamicin complex. Biochem Pharmacol. 1995; 50(11):1749-52. DOI: 10.1016/0006-2952(95)02160-4. View

Maroney A, Glicksman M, Basma A, Walton K, KNIGHT Jr E, Murphy C . Motoneuron apoptosis is blocked by CEP-1347 (KT 7515), a novel inhibitor of the JNK signaling pathway. J Neurosci. 1998; 18(1):104-11. PMC: 6793399. View

Yamasoba T, Nuttall A, Harris C, Raphael Y, Miller J . Role of glutathione in protection against noise-induced hearing loss. Brain Res. 1998; 784(1-2):82-90. DOI: 10.1016/s0006-8993(97)01156-6. View

Ylikoski J, Pirvola U, Virkkala J, Suvanto P, Liang X, Magal E . Guinea pig auditory neurons are protected by glial cell line-derived growth factor from degeneration after noise trauma. Hear Res. 1998; 124(1-2):17-26. DOI: 10.1016/s0378-5955(98)00095-1. View

10.

Saunders J, Cohen Y, Szymko Y . The structural and functional consequences of acoustic injury in the cochlea and peripheral auditory system: a five year update. J Acoust Soc Am. 1991; 90(1):136-46. DOI: 10.1121/1.401307. View

11.

Basile A, Huang J, Xie C, Webster D, Berlin C, Skolnick P . N-methyl-D-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss. Nat Med. 1996; 2(12):1338-43. DOI: 10.1038/nm1296-1338. View

12.

Yuen E, Mobley W . Therapeutic potential of neurotrophic factors for neurological disorders. Ann Neurol. 1996; 40(3):346-54. DOI: 10.1002/ana.410400304. View

13.

Vago P, Humbert G, Lenoir M . Amikacin intoxication induces apoptosis and cell proliferation in rat organ of Corti. Neuroreport. 1998; 9(3):431-6. DOI: 10.1097/00001756-199802160-00014. View

14.

Keithley E, Ma C, Ryan A, Louis J, Magal E . GDNF protects the cochlea against noise damage. Neuroreport. 1998; 9(10):2183-7. DOI: 10.1097/00001756-199807130-00007. View

15.

Saunders J, Canlon B, Flock A . Changes in stereocilia micromechanics following overstimulation in metabolically blocked hair cells. Hear Res. 1986; 24(3):217-25. DOI: 10.1016/0378-5955(86)90020-1. View

16.

Quirk W, Shivapuja B, Schwimmer C, Seidman M . Lipid peroxidation inhibitor attenuates noise-induced temporary threshold shifts. Hear Res. 1994; 74(1-2):217-20. DOI: 10.1016/0378-5955(94)90189-9. View

17.

Dickens M, Rogers J, Cavanagh J, Raitano A, Xia Z, Halpern J . A cytoplasmic inhibitor of the JNK signal transduction pathway. Science. 1997; 277(5326):693-6. DOI: 10.1126/science.277.5326.693. View

18.

Fredelius L, Rask-Andersen H, Johansson B, Urquiza R, Bagger-Sjoback D, Wersall J . Time sequence of degeneration pattern of the organ of Corti after acoustic overstimulation. A light microscopical and electrophysiological investigation in the guinea pig. Acta Otolaryngol. 1988; 106(1-2):81-93. DOI: 10.3109/00016488809107374. View

19.

Ernfors P, Duan M, ElShamy W, Canlon B . Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3. Nat Med. 1996; 2(4):463-7. DOI: 10.1038/nm0496-463. View

20.

Johnson Jr E, Deckwerth T . Molecular mechanisms of developmental neuronal death. Annu Rev Neurosci. 1993; 16:31-46. DOI: 10.1146/annurev.ne.16.030193.000335. View