Ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants

Abstract

The mechanism of the ototoxicity caused by cisplatin is based in the generation of reactive oxygen species, which interferes with the antioxidant protection of the organ of Corti. Conversely, the protection of the cochlea with antioxidants ameliorates the ototoxicity by cisplatin. The ototoxicity produced by cisplatin can be reversible or persistent, depending on the age of the patient, cumulative doses, number of chemotherapy cycles, history of noise exposure, and deteriorating renal function. We have obtained in rats an ototoxic chart utilizing cisplatin (10 mg/kg body weight injected intraperitoneally, once only). Together with this treatment, the animals were treated with melatonin in the drinking water (10 mg/L) or injected subcutaneously (250 microg), and with an antioxidant mixture, injected subcutaneously, composed of 0.25 mg alpha-tocopherol acid succinate, 3 mg ascorbic acid, 1 mg glutathione, and 60 mg N-acetylcysteine. The distortion product otoacoustic emissions were determined for a prolonged period of time for each animal. The ototoxicity produced by cisplatin was maximal from days 7 to 10 post-treatment, returning to normal values in a month. When melatonin and the antioxidant mixture were present, the recovery was between days 10 and 15 post-treatment, independent of the means of administration of the pineal product. We conclude that the ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants.

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

“…Likewise, the inter-individual variability in susceptibility to the ototoxic effect observed in our animals could also be explained by the previous hypotheses. A variety of antioxidants have been shown to attenuate cisplatin-induced apoptosis in the organ of Corti (Lopez-Gonzalez et al, 2000;Rybak and Kelly, 2003). Thus, several strategies have been suggested to prevent the oxidative stress-induced apoptosis of OHCs that have been exposed to cisplatin: prevention of the formation of ROS either by binding the toxin or reversing the binding of the toxin, inhibition of the lipid peroxidation, addition of exogenous free-radical scavengers and antioxidant enzymes, inhibitors of caspases and gene therapy (to upregulate antiapoptotic gene products such as Bcl-2) (Lopez-Gonzalez et al, 2000;Rybak and Kelly, 2003).…”

The role of hyperbaric oxygen therapy (HOT) as an otoprotection agent against cisplatin ototoxicity

“…Drugs like fosfomycin, sulfur compounds, sodium thiosulfate, diethyl carbamate, adrenocorticotropic hormone (ACTH) and derivatives, 4-methylthiobenzoic acid, lipoic acid, glutathione and esters, metionine, alpha-melanocytic stimulating hormone (melatonin) and anti-oxidants like ginkgo biloba extracts, all anti-free radicals, were effectively tested. 11,[14][15][16][17][18][19][20] Hyperbaric oxygen therapy (HOT), having an important anti-oxidant activity is being increasingly used and it is based on inhalation of 100% oxygen under pressures above 1 atm. It is precisely indicated as a stimulant of wound healing and cellular growth.…”

The Protective Role of Molsidomine on the Cisplatin-Induced Ototoxicity

“…DPOAEs measurement is non-invasive and objective to define the early stages of sound processing and assess the biomechanical activity of the outer hair cells [28]. DPOAE measurement is a clear method for identifying the effects of cisplatin on the cochlea before the changes that are identified by pure-tone audiometry [29].…”