Evaluation of geranylgeranylacetone against cisplatin-induced ototoxicity by auditory brainstem response, heat shock proteins and oxidative levels in guinea pigs

Neurotoxicol Teratol. 2017 May:61:29-35. doi: 10.1016/j.ntt.2017.03.004. Epub 2017 Mar 24.

Abstract

This study aims to assess whether geranylgeranylacetone (GGA) could reduce ototoxicity induced by cisplatin through upregulation of not only heat shock protein(HSP)-70, but also HSP-27 and HSP-40, and to study if GGA would reduce cisplatin-induced increase in oxidative stress. 48 guinea pigs were used in this study and treated with the following regimen: 0.5% CMC (sodium carboxymethyl cellulose) control for 7days, GGA (600mg/kg/d) for 7days, a combination of GGA (600mg/kg) for 7days and then one dose of 10mg/kg cisplatin (GGA+Cis), and a combination of CMC for 7days and then 10mg/kg cisplatin (cisplatin group). Auditory brainstem response (ABR) measurement was performed in each animal at time before treatment and 7days after the last dose. Additionally, HSPs, nitric oxide (NO), and lipid peroxidation (LPO) levels in cochlear membranous tissues were assessed. The mean ABR thresholds in the cisplatin group were significantly (p<0.05) increased when compared to the other three groups. In guinea pigs receiving both GGA and cisplatin, the mean threshold shift (TS) were smaller (p<0.05) than those of the cisplatin group, but larger (p<0.05) than those of the CMC control or GGA only group with statistical significance. Compared to the GGA only group or the group treated with GGA+Cis, the cisplatin group had the highest (p<0.05) oxidative stress (NO and LPO levels), and the lowest (p<0.05) mean HSPs expression levels. It can be concluded that GGA attenuate ototoxicity induced by cisplatin through upregulation of HSP-27, -40, and -70. Moreover, increased oxidative stress induced by cisplatin in the cochlea membranous tissue could be reduced by pre-treatment of GGA.

Keywords: Auditory brainstem response; Geranylgeranylacetone; Lipid peroxidation; Nitric oxide; Threshold shift.

MeSH terms

  • Animals
  • Cisplatin / antagonists & inhibitors
  • Cisplatin / toxicity*
  • Cochlea / metabolism
  • Diterpenes / pharmacology*
  • Evoked Potentials, Auditory, Brain Stem / drug effects*
  • Guinea Pigs
  • Hearing Disorders / chemically induced
  • Hearing Disorders / metabolism*
  • Hearing Disorders / physiopathology*
  • Heat-Shock Proteins / metabolism*
  • Lipid Peroxidation
  • Male
  • Nitric Oxide / metabolism
  • Oxidative Stress / drug effects*

Substances

  • Diterpenes
  • Heat-Shock Proteins
  • Nitric Oxide
  • Cisplatin
  • geranylgeranylacetone