Document Detail


Cisplatin ototoxicity blocks sensory regeneration in the avian inner ear.
MedLine Citation:
PMID:  20203207     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cisplatin is a chemotherapeutic agent that is widely used in the treatment of solid tumors. Ototoxicity is a common side effect of cisplatin therapy and often leads to permanent hearing loss. The sensory organs of the avian ear are able to regenerate hair cells after aminoglycoside ototoxicity. This regenerative response is mediated by supporting cells, which serve as precursors to replacement hair cells. Given the antimitotic properties of cisplatin, we examined whether the avian ear was also capable of regeneration after cisplatin ototoxicity. Using cell and organ cultures of the chick cochlea and utricle, we found that cisplatin treatment caused apoptosis of both auditory and vestibular hair cells. Hair cell death in the cochlea occurred in a unique pattern, progressing from the low-frequency (distal) region toward the high-frequency (proximal) region. We also found that cisplatin caused a dose-dependent reduction in the proliferation of cultured supporting cells as well as increased apoptosis in those cells. As a result, we observed no recovery of hair cells after ototoxic injury caused by cisplatin. Finally, we explored the potential for nonmitotic hair cell recovery via activation of Notch pathway signaling. Treatment with the gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester failed to promote the direct transdifferentiation of supporting cells into hair cells in cisplatin-treated utricles. Taken together, our data show that cisplatin treatment causes maintained changes to inner ear supporting cells and severely impairs the ability of the avian ear to regenerate either via proliferation or by direct transdifferentiation.
Authors:
Eric L Slattery; Mark E Warchol
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  30     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-03-05     Completed Date:  2010-05-05     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3473-81     Citation Subset:  IM    
Affiliation:
Fay and Carl Simons Center for the Biology of Hearing and Deafness, Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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MeSH Terms
Descriptor/Qualifier:
Amyloid Precursor Protein Secretases / antagonists & inhibitors
Animals
Antineoplastic Agents / toxicity
Apoptosis / drug effects,  physiology
Cell Differentiation / drug effects,  physiology
Cell Proliferation / drug effects
Cells, Cultured
Chick Embryo
Cisplatin / toxicity*
Deafness / chemically induced,  pathology,  physiopathology
Disease Models, Animal
Dose-Response Relationship, Drug
Ear, Inner / drug effects*,  pathology,  physiopathology
Enzyme Inhibitors / pharmacology
Hair Cells, Auditory / drug effects,  pathology
Hair Cells, Vestibular / drug effects,  pathology
Labyrinth Supporting Cells / drug effects,  pathology
Nerve Degeneration / chemically induced*,  pathology,  physiopathology
Nerve Regeneration / drug effects*,  physiology
Neurotoxins / toxicity*
Organ Culture Techniques
Pitch Perception / drug effects,  physiology
Receptors, Notch / drug effects,  metabolism
Grant Support
ID/Acronym/Agency:
P30 DC004665/DC/NIDCD NIH HHS; P30 DC004665-09/DC/NIDCD NIH HHS; P30 DC04665/DC/NIDCD NIH HHS; R01 DC006283/DC/NIDCD NIH HHS; R01 DC006283-06/DC/NIDCD NIH HHS; T32 DC000022/DC/NIDCD NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/Neurotoxins; 0/Receptors, Notch; 15663-27-1/Cisplatin; EC 3.4.-/Amyloid Precursor Protein Secretases
Comments/Corrections

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