 |
||||
|
||||
|
||||
|
||||
Previous Article | Next Article
The Journal of Neuroscience, January 1, 2000, 20(1):43-50
Rescue of Hearing, Auditory Hair Cells, and Neurons by CEP-1347/KT7515, an Inhibitor of c-Jun N-Terminal Kinase Activation
Ulla Pirvola1, 2, Liang Xing-Qun1, 2, Jussi Virkkala2, Mart Saarma1, Chikara Murakata3, Anna Marie Camoratto4, Kevin M. Walton4, and Jukka Ylikoski1, 2 1 Institute of Biotechnology and 2 Department of Otorhinolaryngology, University of Helsinki, Helsinki 00014, Finland, 3 Kyowa Hakko Kogyo Company, Shizuoka 411, Japan, and 4 Cephalon, West Chester, Pennsylvania 19380-4245
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 (Maroney et al., 1998). 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.
Key words: cochlea; noise trauma; aminoglycoside toxicity; cell death; c-Jun; therapy
Copyright © 2000 Society for Neuroscience 0270-6474/0/20143-08$05.00/0
This article has been cited by other articles:
T. Karasawa, Q. Wang, Y. Fu, D. M. Cohen, and P. S. Steyger
TRPV4 enhances the cellular uptake of aminoglycoside antibiotics
J. Cell Sci., September 1, 2008; 121(17): 2871 - 2879.
[Abstract] [Full Text] [PDF]
M. Lahne and J. E. Gale
Damage-Induced Activation of ERK1/2 in Cochlear Supporting Cells Is a Hair Cell Death-Promoting Signal That Depends on Extracellular ATP and Calcium
J. Neurosci., May 7, 2008; 28(19): 4918 - 4928.
[Abstract] [Full Text] [PDF]
J. Wang, J. Ruel, S. Ladrech, C. Bonny, T. R. van de Water, and J.-L. Puel
Inhibition of the c-Jun N-Terminal Kinase-Mediated Mitochondrial Cell Death Pathway Restores Auditory Function in Sound-Exposed Animals
Mol. Pharmacol., March 1, 2007; 71(3): 654 - 666.
[Abstract] [Full Text] [PDF]
H. Laine, A. Doetzlhofer, J. Mantela, J. Ylikoski, M. Laiho, M. F. Roussel, N. Segil, and U. Pirvola
p19Ink4d and p21Cip1 Collaborate to Maintain the Postmitotic State of Auditory Hair Cells, Their Codeletion Leading to DNA Damage and p53-Mediated Apoptosis
J. Neurosci., February 7, 2007; 27(6): 1434 - 1444.
[Abstract] [Full Text] [PDF]
J. Tan and R. K. Shepherd
Aminoglycoside-Induced Degeneration of Adult Spiral Ganglion Neurons Involves Differential Modulation of Tyrosine Kinase B and p75 Neurotrophin Receptor Signaling
Am. J. Pathol., August 1, 2006; 169(2): 528 - 543.
[Abstract] [Full Text] [PDF]
G. M. Kalinec, M. E. Fernandez-Zapico, R. Urrutia, N. Esteban-Cruciani, S. Chen, and F. Kalinec
Pivotal role of Harakiri in the induction and prevention of gentamicin-induced hearing loss
PNAS, November 1, 2005; 102(44): 16019 - 16024.
[Abstract] [Full Text] [PDF]
F. Lallemend, S. Hadjab, G. Hans, G. Moonen, P. P. Lefebvre, and B. Malgrange
Activation of protein kinase C{beta}I constitutes a new neurotrophic pathway for deafferented spiral ganglion neurons
J. Cell Sci., October 1, 2005; 118(19): 4511 - 4525.
[Abstract] [Full Text] [PDF]
R. K. Barr, R. M. Hopkins, P. M. Watt, and M. A. Bogoyevitch
Reverse Two-hybrid Screening Identifies Residues of JNK Required for Interaction with the Kinase Interaction Motif of JNK-interacting Protein-1
J. Biol. Chem., October 8, 2004; 279(41): 43178 - 43189.
[Abstract] [Full Text] [PDF]
R. K. Barr, I. Boehm, P. V. Attwood, P. M. Watt, and M. A. Bogoyevitch
The Critical Features and the Mechanism of Inhibition of a Kinase Interaction Motif-based Peptide Inhibitor of JNK
J. Biol. Chem., August 27, 2004; 279(35): 36327 - 36338.
[Abstract] [Full Text] [PDF]
J. Wang, T. R. Van De Water, C. Bonny, F. de Ribaupierre, J. L. Puel, and A. Zine
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., September 17, 2003; 23(24): 8596 - 8607.
[Abstract] [Full Text] [PDF]
P. P. Roux, G. Dorval, M. Boudreau, A. Angers-Loustau, S. J. Morris, J. Makkerh, and P. A. Barker
K252a and CEP1347 Are Neuroprotective Compounds That Inhibit Mixed-lineage Kinase-3 and Induce Activation of Akt and ERK
J. Biol. Chem., December 13, 2002; 277(51): 49473 - 49480.
[Abstract] [Full Text] [PDF]
M. C Holley
Application of new biological approaches to stimulate sensory repair and protection
Br. Med. Bull., October 1, 2002; 63(1): 157 - 169.
[Abstract] [Full Text] [PDF]
S. M. Lippman and W. K. Hong
Cancer Prevention Science and Practice
Cancer Res., September 15, 2002; 62(18): 5119 - 5125.
[Full Text] [PDF]
J. I. Matsui, J. M. Ogilvie, and M. E. Warchol
Inhibition of Caspases Prevents Ototoxic and Ongoing Hair Cell Death
J. Neurosci., February 15, 2002; 22(4): 1218 - 1227.
[Abstract] [Full Text] [PDF]
C. D. Major and B. A. Wolf
Interleukin-1{beta} Stimulation of c-Jun NH2-Terminal Kinase Activity in Insulin-Secreting Cells: Evidence for Cytoplasmic Restriction
Diabetes, December 1, 2001; 50(12): 2721 - 2728.
[Abstract] [Full Text] [PDF]
Z. Xu, A. C. Maroney, P. Dobrzanski, N. V. Kukekov, and L. A. Greene
The MLK Family Mediates c-Jun N-Terminal Kinase Activation in Neuronal Apoptosis
Mol. Cell. Biol., July 15, 2001; 21(14): 4713 - 4724.
[Abstract] [Full Text] [PDF]
U. Namgung and Z. Xia
Arsenite-Induced Apoptosis in Cortical Neurons Is Mediated by c-Jun N-Terminal Protein Kinase 3 and p38 Mitogen-Activated Protein Kinase
J. Neurosci., September 1, 2000; 20(17): 6442 - 6451.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|