title: Transtympanic administration of short interfering (si)RNA for the NOX3 isoform of NADPH oxidase protects against cisplatin-induced hearing loss in the rat.
abstract: Cisplatin produces hearing loss in cancer patients. Reactive oxygen species (ROS) in the cochlea leads to lipid peroxidation, death of outer hair cells (OHCs), and hearing loss. The cochlea expresses a unique isoform of NADPH oxidase, NOX3, which serves as the primary source of ROS generation in the cochlea. Inhibition of NOX3 could offer a unique protective target against cisplatin ototoxicity. Here, we document that knockdown of NOX3 using short interfering (si) RNA abrogated cisplatin ototoxicity, as evidenced by protection of OHCs from damage and reduced threshold shifts in auditory brainstem responses (ABRs). Transtympanic NOX3 siRNA reduced the expression of NOX3 in OHCs, spiral ganglion (SG) cells, and stria vascularis (SV) in the rat. NOX3 siRNA also reduced the expression of transient receptor potential vanilloid 1 (TRPV1) channel and kidney injury molecule-1 (KIM-1), biomarkers of cochlear damage. Also, transtympanic NOX3 siRNA reduced the expression of Bax, abolished the decrease in expression of Bcl2, and reduced apoptosis induced by cisplatin in the cochlea. These data suggest that NOX3 regulates stress-related genes in the cochlea, such as TRPV1 and KIM-1, and initiates apoptosis in the cochlea. This appears to be the first study of the efficacy of transtympanic delivery of siRNA attenuating cisplatin ototoxicity.
authors.affiliation: Department of Surgery, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9649, USA.
authors.forename: Debashree
authors.initials: D
authors.lastname: Mukherjea
authors.forename: Sarvesh
authors.initials: S
authors.lastname: Jajoo
authors.forename: Tejbeer
authors.initials: T
authors.lastname: Kaur
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Sheehan
authors.forename: Vickram
authors.initials: V
authors.lastname: Ramkumar
authors.forename: Leonard P
authors.initials: LP
authors.lastname: Rybak
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001309:Auditory Threshold / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D018072:Hair Cells, Auditory, Outer / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D034381:Hearing Loss / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; D002945:Cisplatin; D019255:NADPH Oxidases; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050916:TRPV Cation Channels; D051028:bcl-2-Associated X Protein; C494828:Bax protein, rat; C110936:Havcr1 protein, rat; C493922:Trpv1 protein, rat; C534192:Nox3 protein, rat