Adenosine A₁Receptor 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 A 1 receptor (A 1 AR) 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 A 1 AR 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-␣ (TNF-␣) 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-␣, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced cisplatin-mediated apoptosis. These data suggest that the A 1 AR provides otoprotection by suppressing NOX3 and inflammation in the cochlea and could serve as an ideal target for otoprotective drug therapy.

Targeting nitrative stress for attenuating cisplatin-induced downregulation of cochlear LIM domain only 4 and ototoxicity

“…These are good experimental models for studying ototoxicity and have been employed by other researchers to investigate the molecular mechanisms underlying cisplatin-induced ototoxicity [5], [41]. We used fully differentiated UBOC1 cells in all our experiments, which were verified by testing the expression of myosin VIIa, a biomarker of hair cells.…”

“…Therefore, ototoxicity is a major side-effect of cisplatin, which significantly affects the quality of life in cancer survivors and has devastating consequences in children because it affects their speech and language development, education, and social integration [1], [2]. Although progress has been made in delineating the mechanisms underlying cisplatin-induced ototoxicity [3], [4], [5], [6], [7], the signaling pathways that facilitate cochlear apoptosis are yet to be fully characterized. Thus, we do not yet have a comprehensive solution to this important problem.…”

Role of STAT1 and Oxidative Stress in Gentamicin-Induced Hair Cell Death in Organ of Corti

“…R-PIA also reduced the expression of several STAT1 target genes, such as cyclooxygenase-2 (COX-2), TNF-alpha, and inducible nitric oxide synthase (iNOS) and was associated with decreased inflammation and apoptosis in the rat cochlea with preserved hearing. 20 …”

Hearing vulnerability after noise exposure in a mouse model of reactive oxygen species overproduction

“…; Kaur et al . ). Subsequently, a small interfering RNA (siRNA) for Nox3 was reportedly effective in reducing OHC damage and hearing function in rats (Mukherjea et al .…”

“…NADPH oxidase 3 (Nox3), one of the main NOXs in the inner ear, has been found to be increased in the cochlea after administration of cisplatin in rats, which leads to ROS overproduction and induces apoptosis in the cochlea, including OHC (Mukherjea et al 2008;Kaur et al 2016). Subsequently, a small interfering RNA (siRNA) for Nox3 was reportedly effective in reducing OHC damage and hearing function in rats (Mukherjea et al 2010).…”