Published online Aug 28, 2013. doi: 10.5319/wjo.v3.i3.100
Revised: June 27, 2013
Accepted: July 23, 2013
Published online: August 28, 2013
AIM: To investigate a novel pharmacological intervention to mitigate cisplatin ototoxicity using a selective adenosine A1 receptor agonist adenosine amine congener (ADAC).
METHODS: Male Wistar rats (8-10 wk) were exposed to a two-cycle cisplatin treatment similar to clinical course of cancer chemotherapy. Each cycle comprised 4 d of intraperitoneal cisplatin injections (1 mg/kg twice daily) separated by 10 d of rest. ADAC (100 μg/kg) or drug vehicle solution (control) was administered intraperitoneally for 5 d at 24 h intervals during the second cisplatin cycle (Regime 1), or upon completion of the cisplatin treatment (Regime 2). Hearing thresholds were measured using auditory brainstem responses (ABR) before cisplatin administration (baseline) and 7 d after the end of cisplatin treatment. Histological analysis of cochlear tissues included hair cell counting and qualitative assessment of apoptosis using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL) staining.
RESULTS: ABR threshold shifts in cisplatin-treated Wistar rats ranged from 5-29 dB across the frequency range used in the study (4-24 kHz). Higher frequencies (16-24 kHz) were mostly affected by cisplatin ototoxicity (mean threshold shift 25-29 dB). ADAC treatment during the second cisplatin cycle reduced cisplatin-induced threshold shifts by 12-16 dB (P < 0.01) at higher frequencies compared to control vehicle-treated rats. However, the treatment was ineffective if ADAC administration was delayed until after the completion of the cisplatin regime. Functional recovery was supported by increased survival of hair cells in the cochlea. Qualitative analysis using TUNEL staining demonstrated reduced apoptosis of the outer hair cells and marginal cells in the stria vascularis in animals treated with ADAC during the second cisplatin cycle.
CONCLUSION: A1 adenosine receptor agonist ADAC mitigates cisplatin-induced cochlear injury and hearing loss, however its potential interference with antineoplastic effects of cisplatin needs to be established.
Core tip: This study investigated a novel pharmacological intervention to mitigate cisplatin ototoxicity using systemic administration of a selective adenosine A1 receptor agonist adenosine amine congener (ADAC). Our study demonstrates that systemic administration of ADAC confers partial protection from cisplatin-induced ototoxicity. In rats exposed to cisplatin, ADAC ameliorated high frequency hearing loss, improved the survival of the outer hair cells and reduced apoptosis of the outer hair cells and marginal cells in the stria vascularis. This study provides support for the otoprotective role of ADAC with potential clinical benefits extending from noise-induced hearing loss to cisplatin ototoxicity.