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| Cochlear
Pathology and Therapy
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Inner (IHCs) and outer (OHCs) sensory hair
cells disappear after acoustic trauma, ototoxic treatments
and during aging, causing irreversible hearing deficits. Hair
cell loss induces further disappearance of both non-sensory
supporting cells and spiral ganglion neurons preventing any
possibility for hearing restoration. Our goals are to identify
mechanisms of cell death and repair in the damaged cochlea
in order to define cellular and molecular targets for experimental
therapies aimed at protecting and regenerating hair cells
and auditory neurons.
Macrophage contribution
to cell death and/or cell repair is investigated in
the amikacin-deafened rat cochlea (Figure 1) since they
could become targets for experimental therapies aimed
at preventing cell death and/or promoting cell regeneration.
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Figure 1. Quantification
of the macrophage invasion of the rat cochlea after
amikacin intoxication. |
We have shown that apoptotic pathways involving
caspases 3, caspases 9 and calpains are activated in cells
in response to extracellular signals and internal insults
(Figure 2). We thus designed highly effective therapeutic
strategies, using intra-cochlear applications of specific
TAT-coupled peptide inhibitors of JNK, caspases or calpains,
to prevent sensory cell death and/or to rescue hearing function
vivo (Figure 3).
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| Figure 2. Caspases 9 (green)
expression in a sound traumatized guinea-pig cochlea.
Hair cells are immunostained for calbindin (red). |
Figure 3.
Audiograms (A) and quantitative analysis of hair cell
damage (B) from cochleas perfused with 100 µM
D-JNKI-1 (blue circles) and from contralateral untreated
cochleas (red circles) after an acoustic trauma. While
control cochleas displayed a permanent 40 dB hearing
loss, a significant protection can be seen in D-JNKI-1-treated
cochleas. |
In order to try to regenerate new sensory
cells, the efficacy of various vectors (liposome, viral vectors,
and plasmids) is tested. Preliminary experiments show that
adenovirus can transfect hair cells in the organ of Corti,
and cells of the stria vascularis (Figure 4). Morphological
and functional monitoring are done to assess potential deleterious
effects, and possible ways to prevent them.
Figure
4. In vivo transfection of the cochlea
with Ad5 ?E1-E3/CMV/GFP. A. Transgene expression (green)
was observed in mesothelial cells of the scala tympani
(ST) and scala vestibuli (SV), Schwann cells, cells
of the basilar (bm) and Reissner’s membranes (Rm)
and cells of the stria vascularis (sva). B: In some
animals, GFP was also observed in the inner and outer
hair cells. C. Stria vascularis cells (sva) with transduced
cells. Sensory hair cells and neurons are identified
by their parvalbumine immunoreactivity (red). |
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Selected recent references:
Wang J, Ruel J, Ladrech S, Bonny C, van de Water TR,
Puel JL. Inhibition of the c-Jun N-terminal kinase-mediated
mitochondrial cell death pathway restores auditory function
in sound-exposed animals. Mol. Pharmacol. 2007, 71: 654-666.
Wang J, Ladrech S, Pujol R, Brabet P, Van De Water
TR, Puel JL. Caspase inhibitors, but not c-Jun NH2-terminal
kinase inhibitor treatment, prevent cisplatin-induced hearing
loss. Cancer Res. 2004, 64: 9217-9224.
Ladrech S, Guitton M, Saido T, Lenoir M. Calpain
activity in the amikacin-damaged rat cochlea. J. Comp. Neurol.
2004, 477: 149-160.
Wang J, Van De Water TR, Bonny C, de Ribaupierre F,
Puel JL, 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: 8596-8607.
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