A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma.
Free radical and calcium buffering mechanisms are implicated in cochlear cell damage that has been induced by sound trauma. Thus in this study we evaluated the therapeutic effect of a novel dual inhibitor of calpains and of lipid peroxidation (BN 82270) on the permanent hearing and hair cell loss induced by sound trauma. Perfusion of BN 82270 into the scala tympani of the guinea pig cochlea prevented the formation of calpain-cleaved fodrin, translocation of cytochrome c, DNA fragmentation and hair cell degeneration caused by sound trauma. This was confirmed by functional tests in vivo, showing a clear dose-dependent reduction of permanent hearing loss (ED50 = 4.07 microM) with almost complete protection at 100 microM. Furthermore, BN82270 still remained effective even when applied onto the round window membrane after sound trauma had occurred, within a therapeutic window of 24 h. This indicates that BN 82270 may be of potential therapeutic value in treating the cochlea after sound trauma.
Wang
Jing
J
INSERM U583, Laboratoire de Physiopathologie et Thérapie des Déficits Sensoriels et Moteurs, Montpellier, France.
Pignol
Bernadette
B
Chabrier
Pierre-Etienne
PE
Saido
Takaomi
T
Lloyd
Ruth
R
Tang
Yong
Y
Lenoir
Marc
M
Puel
Jean-Luc
JL
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002154:Calpain / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins / Q000378:metabolism; D003051:Cochlea / Q000201:enzymology / Q000293:injuries* / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006317:Hearing Loss, Noise-Induced / Q000473:pathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects*; D008840:Microfilament Proteins / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D012405:Round Window, Ear / Q000473:pathology; D014432:Tympanic Membrane / Q000187:drug effects; D013049:Spectrin
D002154:Calpain; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D045304:Cytochromes c; D004151:Dipeptides; D008840:Microfilament Proteins; D013049:Spectrin