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

Pirvola, Ulla; Liang, Xiaofang; Virkkala, Jussi; Saarma, Märt; Murakata, Chikara; Camoratto, Anna Marie; Walton, Kenneth G.; Ylikoski, Jukka

doi:10.1523/jneurosci.20-01-00043.2000

Cited by 296 publications

(265 citation statements)

References 50 publications

(64 reference statements)

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“…Further research into the role of GADD45b in hair cells is needed to substantiate this hypothesis, however. It is also possible that NF-kB is involved in regulation of the cellular antioxidant program in the cochlea, as it has been proposed for neuronal cells and other cell types that harbor NF-kB in a constitutive activated state (Schü tze et al 1992;Kaltschmidt et al 1994;Lezoualch'l et al 1998;Jang and Surh 2004).…”

Section: Discussionmentioning

confidence: 97%

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NF-κB is Required for Survival of Immature Auditory Hair Cells In Vitro

Nagy

Monge

Albinger-Hegyi

et al. 2005

JARO

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Damage to auditory hair cells in the inner ear as a consequence of aging, disease, acoustic trauma, or exposure to ototoxins underlies most cases of hearing impairment. Because the mammalian ear cannot replace damaged hair cells, loss of hearing is irreversible and progressive throughout life. One of the current goals of inner ear biology is to develop therapeutic strategies to prevent hair cell degeneration. Although important progress has been made in discovering factors that mediate hair cell death, very little is known about the molecular pathway(s) that signal survival. Here we considered the role of NF-kB, a ubiquitous transcription factor that plays a major role in the regulation of many apoptosis-and stressrelated genes, in mediating hair cell survival. NF-kB was detected in a constitutively active form in the organ of Corti of 5-day-old rats. Selective inhibition of NF-kB through use of a cell-permeable inhibitory peptide in vitro caused massive degeneration of hair cells within 24 h of inhibitor application. Hair cell death occurred through an apoptotic pathway through activation of caspase-3 and may involve transcriptional down-regulation of the gadd45b gene, an anti-apoptotic NF-kB target. In view of our results, it seems likely that NF-kB may participate in normal hair cell function.Keywords: apoptosis, inhibitor of kB, inner ear, organ of Corti, RelAAbbreviations: a -antibody; bp -base pair; BSAbovine serum albumin; CHAPS -3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate; DMSO -dimethyl sulfoxide; DTT -dithiothreitol; EDTA -ethylendiaminetetraacetic acid; EGTA -ethylenglycol-bis(b-aminoethyl)-N,N,N 0 ,N 0 -tetraacetic acid; FITC -fluorescein isothiocyanate; GADD45b -growth arrest and DNA damage-inducible 45b protein; GAPDH -glyceraldehydes-3-phosphate dehydrogenase protein; HEPES -N-2-Hydroxyethylpiperazine-N 0 -2-ethanesulfonic acid; IB -immunoblotting; IHC -inner hair cell; IkB -inhibitor of kB protein; INH -Synthetic inhibitor of NF-kB protein; INHMut -synthetic inactive control for the inhibitor of NF-kB protein; JNK -c-Jun N-terminal kinase; MIPmultiple image processing; NF-kB -nuclear factor-kB; NT -not treated; OC -organ of Corti; OHC -outer hair cell; p5 -postnatal day 5; PBS -phosphate-buffered saline; PMSF -phenylYmethyl-sulfonyl fluoride; PNT -parthenolide; Rel -reticuloendotheliosis viral oncogene homologue; RT -reverse transcriptase; SG -spiral ganglion; SV -stria vascularis; XIAP -Xlinked inhibitor of apoptosis protein.

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Section: Discussionmentioning

confidence: 97%

“…Studies show that reactive oxygen species (ROS) and activated c-Jun N-terminal kinase ( JNK) signaling are some of the key mediators of hair cell death (Clerici et al 1996;Huang et al 2000;Pivola et al 2000;Sha and Schacht 1999). However, surprisingly little is known about the factors that signal hair cell survival.…”

Section: Introductionmentioning

confidence: 99%

NF-κB is Required for Survival of Immature Auditory Hair Cells In Vitro

Nagy

Monge

Albinger-Hegyi

et al. 2005

JARO

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“…prevented by the application of JNK inhibitors (Pirvola et al 2000;Bodmer et al 2002b;Ylikoski et al 2002). Other recent evidence suggests that the intracellular signals leading to JNK activation in hair cells include the small G proteins Ras and Rac/cdc42 (Bodmer et al 2002a).…”

Section: Journal Of the Association For Research In Otolaryngologymentioning

confidence: 99%

A PI3K Pathway Mediates Hair Cell Survival and Opposes Gentamicin Toxicity in Neonatal Rat Organ of Corti

Chung

Pak²,

Lin³

et al. 2006

JARO

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“…There are growing numbers of compounds that have been found to protect the cochlea from gentamicin toxicity (Yokota et al 1989;Garetz et al 1994;Xuan and Dong 1995;Song et al 1998;Gao 1999;Sha and Schacht 1999;Suzuki et al 2000;Sinswat et al 2000;Pirvola et al 2000). It is generally assumed that the protective effects of these compounds are due to direct effects upon hair cells.…”

Section: Implications For Protective Measuresmentioning

confidence: 99%

Changes in Cytochemistry of Sensory and Nonsensory Cells in Gentamicin-Treated Cochleas

Imamura

Adams

2003

JARO - Journal of the Association for Research in Otolaryngolog

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Effects of a single local dose of gentamicin upon sensory and nonsensory cells throughout the cochlea were assessed by changes in immunostaining patterns for a broad array of functionally important proteins. Cytochemical changes in hair cells, spiral ganglion cells, and cells of the stria vascularis, spiral ligament, and spiral limbus were found beginning 4 days post administration. The extent of changes in immunostaining varied with survival time and with cell type and was not always commensurate with the degree to which individual cell types accumulated gentamicin. Outer hair cells, types I and II fibrocytes of the spiral ligament, and fibrocytes in the spiral limbus showed marked decreases in immunostaining for a number of constituents. In contrast, inner hair cells, type III fibrocytes and root cells of the spiral ligament, cells of the stria vascularis, and interdental cells in the spiral limbus showed less dramatic decreases, and in some cases they showed increases in immunostaining. Results indicate that, in addition to damaging sensory cells, local application of gentamicin results in widespread and disparate disruptions of a variety of cochlear cell types. Only in the case of ganglion cells was it apparent that the changes in nonsensory cells were secondary to loss or damage of hair cells. These results indicate that malfunction of the ear following gentamicin treatment is widespread and far more complex than simple loss of sensory elements. The results have implications for efforts directed toward detecting, preventing, and treating toxic effects of aminoglycosides upon the inner ear.

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

Cited by 296 publications

References 50 publications

NF-κB is Required for Survival of Immature Auditory Hair Cells In Vitro

NF-κB is Required for Survival of Immature Auditory Hair Cells In Vitro

A PI3K Pathway Mediates Hair Cell Survival and Opposes Gentamicin Toxicity in Neonatal Rat Organ of Corti

Changes in Cytochemistry of Sensory and Nonsensory Cells in Gentamicin-Treated Cochleas

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