WR-2721 (Amifostine) Ameliorates Cisplatin-Induced Hearing Loss But Causes Neurotoxicity In Hamsters: Dose-Dependent Effects

Abstract

Chemoprotective agents reduce the toxic side effects of chemotherapy agents such as cisplatin. The conventional belief is that the chemoprotective agent WR-2721 (Amifostine), while protecting against most cisplatin-induced side effects, does not protect against cisplatin-induced ototoxicity (i.e., hearing loss). There is no knowledge, however, about the efficacy of high doses of WR-2721 (WR) in possibly protecting against cisplatin-induced ototoxicity. Thus, the dose-dependent effects of WR in possibly ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 18, 40, 80, or 400 mg/kg/injection of the rescue agent WR (n = 5 or 10/group). Other groups received either 80 mg/kg/injection WR alone (n = 5) or were untreated (n = 14). Ototoxicity was assessed by auditory brain stem responses (ABR). WR provided dose-dependent rescue from cisplatin's ototoxicity with no protection at the low dose of 18 mg/ kg, moderate protection at 40 mg/kg, and nearly complete protection at 80 and 400 mg/kg. However, WR doses of 40 mg/kg or higher caused neurotoxicity as evidenced by prolongations in the ABR's interpeak latencies. Thus, high doses of WR provided the beneficial effect of protecting against cisplatininduced ototoxicity, but had the harmful side effect of neurotoxicity. Previous failures to find chemoprotection from cisplatin-induced ototoxicity were likely due to the use of WR doses that were too small. The clinical implications of the beneficial and harmful effects of high doses of WR are discussed.

Reduced auditory acuity in rat pups from excess and deficient omega-3 fatty acid consumption by the mother

“…Specifically, ABR thresholds were the highest (worst) for the 2 kHz tone pip condition and got progressively lower (better) as tone pip frequency increased to 4 kHz, 8 kHz and 16 kHz. These results reflect the fact that rats have relatively poor hearing at 2 kHz and good hearing at 16 kHz [13]. There were no significant interactions with the Tone Pip, Group or Sex conditions.…”

“…The rat ABR is composed of four vertex-positive waves (labeled P1 to P4) occurring within 6 ms of stimulus onset [13]. These ABR waves are generated by a series of action potentials and post-synaptic potentials ascending the lower portion of the auditory pathway.…”

“…Our study's primary goal was to further investigate the possibility that excess ω-3 FA consumption, in the absence of methyl mercury and other environmental contaminants, during pregnancy and lactation results in auditory and neural toxicity as evidenced by the ABR. The ABR is a sensitive measure of peripheral and central neurotoxicity, auditory function [13] and brain maturation [16]. We sought to expand the findings of Stockard and colleagues [20,40,44] by adding a deficient ω-3 FA group as a negative control group, using different tone pip frequencies instead of click stimuli to see at which tonal frequencies beneficial and/or adverse effects occur, controlling for the confounding variables of body temperature and within-litter effects, and looking at ABR thresholds instead of ABR latencies.…”

“…We sought to expand the findings of Stockard and colleagues [20,40,44] by adding a deficient ω-3 FA group as a negative control group, using different tone pip frequencies instead of click stimuli to see at which tonal frequencies beneficial and/or adverse effects occur, controlling for the confounding variables of body temperature and within-litter effects, and looking at ABR thresholds instead of ABR latencies. ABR thresholds are a measure of a subject's hearing acuity [13,15]. That is, it can tell us who has a hearing loss, how much of a hearing loss and at which tonal frequencies.…”

The Protective Effect of Chrysin Against Cisplatin İnduced Ototoxicity in Rats

“…Amelioration of cisplatin-induced ototoxicity has been demonstrated in studies, with many reporting on the protective effect of antioxidant agents, such as caffeic acid phenethyl ester [5], D-methionine [6], dexamethasone [7], neurotropines [8], flunarizine [9], amifostine [10], N-acetyl cysteine [11,12], erdosteine [13], salicylates [14], gingko biloba extract [15], allopurinol, ebselen [16], resveratrol [4,17], thymoquinone [18], betaglucan [19], and lycopene [20].…”