title: Adenosine A1 Receptor Protects Against Cisplatin Ototoxicity by Suppressing the NOX3/STAT1 Inflammatory Pathway in the Cochlea.
abstract: Cisplatin is a commonly used antineoplastic agent that produces ototoxicity that is mediated in part by increasing levels of reactive oxygen species (ROS) via the NOX3 NADPH oxidase pathway in the cochlea. Recent studies implicate ROS generation in mediating inflammatory and apoptotic processes and hearing loss by activating signal transducer and activator of transcription (STAT1). In this study, we show that the adenosine A1 receptor (A1AR) protects against cisplatin ototoxicity by suppressing an inflammatory response initiated by ROS generation via NOX3 NADPH oxidase, leading to inhibition of STAT1. Trans-tympanic administration of the A1AR agonist R-phenylisopropyladenosine (R-PIA) inhibited cisplatin-induced ototoxicity, as measured by auditory brainstem responses and scanning electron microscopy in male Wistar rats. This was associated with reduced NOX3 expression, STAT1 activation, tumor necrosis factor-α (TNF-α) levels, and apoptosis in the cochlea. In vitro studies in UB/OC-1 cells, an organ of Corti immortalized cell line, showed that R-PIA reduced cisplatin-induced phosphorylation of STAT1 Ser(727) (but not Tyr(701)) and STAT1 luciferase activity by suppressing the ERK1/2, p38, and JNK mitogen-activated protein kinase (MAPK) pathways.R-PIA also decreased the expression of STAT1 target genes, such as TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced cisplatin-mediated apoptosis. These data suggest that the A1AR provides otoprotection by suppressing NOX3 and inflammation in the cochlea and could serve as an ideal target for otoprotective drug therapy.
  
  
  CONCLUSIONS
  Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. Its use results in significant and permanent hearing loss, for which no US Food and Drug Administration-approved treatment is currently available. In this study, we targeted the cochlear adenosine A1 receptor (A1AR) by trans-tympanic injections of the agonist R-phenylisopropyladenosine (R-PIA) and showed that it reduced cisplatin-induced inflammation and apoptosis in the rat cochlea and preserved hearing. The mechanism of protection involves suppression of the NOX3 NADPH oxidase enzyme, a major target of cisplatin-induced reactive oxygen species (ROS) generation in the cochlea. ROS initiates an inflammatory and apoptotic cascade in the cochlea by activating STAT1 transcription factor, which is attenuated byR-PIA. Therefore, trans-tympanic delivery of A1AR agonists could effectively treat cisplatin ototoxicity.
authors.affiliation: Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri 63110, and.
authors.forename: Tejbeer
authors.initials: T
authors.lastname: Kaur
authors.affiliation: Department of Pharmacology and.
authors.forename: Vikrant
authors.identifier: http://orcid.org/0000-0003-4996-7282
authors.initials: V
authors.lastname: Borse
authors.affiliation: Department of Pharmacology and.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sheth
authors.affiliation: Department of Surgery, Southern Illinois University School of Medicine, Springfield, Illinois 62794.
authors.forename: Kelly
authors.identifier: http://orcid.org/0000-0001-8131-2820
authors.initials: K
authors.lastname: Sheehan
authors.affiliation: Department of Pharmacology and.
authors.forename: Sumana
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Pharmacology and.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Tupal
authors.affiliation: Department of Pharmacology and.
authors.forename: Sarvesh
authors.initials: S
authors.lastname: Jajoo
authors.affiliation: Department of Surgery, Southern Illinois University School of Medicine, Springfield, Illinois 62794.
authors.forename: Debashree
authors.identifier: http://orcid.org/0000-0001-5092-9860
authors.initials: D
authors.lastname: Mukherjea
authors.affiliation: Department of Pharmacology and Department of Surgery, Southern Illinois University School of Medicine, Springfield, Illinois 62794.
authors.forename: Leonard P
authors.identifier: http://orcid.org/0000-0002-9365-5924
authors.initials: LP
authors.lastname: Rybak
authors.affiliation: Department of Pharmacology and vramkumar@siumed.edu.
authors.forename: Vickram
authors.initials: V
authors.lastname: Ramkumar
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000187:drug effects; D006311:Hearing Disorders / Q000139:chemically induced / Q000503:physiopathology; D007249:Inflammation / Q000503:physiopathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D019255:NADPH Oxidases / Q000187:drug effects* / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000187:drug effects*; D050794:STAT1 Transcription Factor / Q000187:drug effects* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000970:Antineoplastic Agents; D043682:Receptor, Adenosine A1; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D014409:Tumor Necrosis Factor-alpha; D019255:NADPH Oxidases; C534192:Nox3 protein, rat; D002945:Cisplatin
keywords: STAT1; adenosine; adenosine receptors; cisplatin; hearing loss; inflammation