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. SIGNIFICANCE STATEMENT:
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Authors | Tejbeer Kaur, Vikrant Borse, Sandeep Sheth, Kelly Sheehan, Sumana Ghosh, Srinivasan Tupal, Sarvesh Jajoo, Debashree Mukherjea, Leonard P Rybak, Vickram Ramkumar |
Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience
(J Neurosci)
Vol. 36
Issue 14
Pg. 3962-77
(Apr 06 2016)
ISSN: 1529-2401 [Electronic] United States |
PMID | 27053204
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2016 the authors 0270-6474/16/363962-16$15.00/0. |
Chemical References |
- Adenosine A1 Receptor Agonists
- Adenosine A1 Receptor Antagonists
- Antineoplastic Agents
- Receptor, Adenosine A1
- STAT1 Transcription Factor
- Stat1 protein, rat
- Tumor Necrosis Factor-alpha
- NADPH Oxidases
- Nox3 protein, rat
- Cisplatin
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Topics |
- Adenosine A1 Receptor Agonists
(administration & dosage, pharmacology)
- Adenosine A1 Receptor Antagonists
(administration & dosage, pharmacology)
- Animals
- Antineoplastic Agents
(toxicity)
- Cell Line
- Cisplatin
(toxicity)
- Cochlea
(drug effects)
- Evoked Potentials, Auditory, Brain Stem
(drug effects)
- Hair Cells, Auditory
(drug effects)
- Hearing Disorders
(chemically induced, physiopathology)
- Inflammation
(physiopathology)
- MAP Kinase Signaling System
(drug effects)
- Male
- NADPH Oxidases
(drug effects, genetics)
- Rats
- Rats, Wistar
- Receptor, Adenosine A1
(drug effects)
- STAT1 Transcription Factor
(drug effects, genetics)
- Signal Transduction
(drug effects)
- Tumor Necrosis Factor-alpha
(metabolism)
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