NOX3 NADPH oxidase couples transient receptor potential vanilloid 1 to signal transducer and activator of transcription 1-mediated inflammation and hearing loss.
Transient receptor potential vanilloid 1 (TRPV1) is implicated in cisplatin ototoxicity. Activation of this channel by cisplatin increases reactive oxygen species generation, which contribute to loss of outer hair cells in the cochlea. Knockdown of TRPV1 by short interfering RNA protected against cisplatin ototoxicity. In this study, we examined the mechanism underlying TRPV1-mediated ototoxicity using cultured organ of Corti transformed cells (UB/OC-1) and rats. Trans-tympanic injections of capsaicin produced transient hearing loss within 24 h, which recovered by 72 h. In UB/OC-1 cells, capsaicin increased NOX3 NADPH oxidase activity and activation of signal transducer and activator of transcription 1 (STAT1). Intratympanic administration of capsaicin transiently increased STAT1 activity and expression of downstream proinflammatory molecules. Capsaicin produced a transient increase in CD14-positive inflammatory cells into the cochlea, which mimicked the temporal course of STAT1 activation but did not alter the expression of apoptotic genes or damage to outer hair cells. In addition, trans-tympanic administration of STAT1 short interfering RNA protected against capsaicin-induced hearing loss. These data suggest that activation of TRPV1 mediates temporary hearing loss by initiating an inflammatory process in the cochlea via activation of NOX3 and STAT1. Thus, these proteins represent reasonable targets for ameliorating hearing loss.
Mukherjea
Debashree
D
Department of Pharmacology, SIU School of Medicine, Springfield, Illinois 62794-9629, USA.
Jajoo
Sarvesh
S
Sheehan
Kelly
K
Kaur
Tejbeer
T
Sheth
Sandeep
S
Bunch
Jennifer
J
Perro
Christopher
C
Rybak
Leonard P
LP
Ramkumar
Vickram
V
D000818:Animals; D002211:Capsaicin / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism; D005071:Evoked Potentials; D034381:Hearing Loss / Q000139:chemically induced / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D019255:NADPH Oxidases; D002211:Capsaicin