Ototoxicity of 12 mg/kg cisplatin in the Fischer 344/NHsd rat using multiple dosing strategies

Abstract

Ototoxicity continues to be a major dose-limiting side effect of cis-diamminedichloroplatinum(II) (cisplatin). With an ongoing need to develop pharmaceutical protection strategies for cisplatin's ototoxicity, there is also a need to develop stable in-vivo mammalian models of cisplatin ototoxicity. The current study examined the difference in ototoxicity of a cumulative 12 mg/kg dose of cisplatin in the Fischer 344/NHsd rat when administered over four different dosing protocols. Hearing sensitivity was measured using free-field auditory brainstem response thresholds under anesthesia. Rats were divided into four groups. The first group was administered 12 mg/kg of cisplatin in a single bolus infusion. The second group was administered two 6 mg/kg infusions separated by 7 days. The third group was administered 3 mg/kg injections once per day for 4 consecutive days. The fourth group was administered 3 mg/kg injections in four injections separated by 3 days each. Hearing thresholds and body weights were measured at 3 and 7 days after the final cisplatin exposure. Postmortem sensory cell counts were used to confirm injury to the auditory system. The 4 consecutive days of 3 mg/kg induced a greater mortality rate and greater hearing loss at day 3 than the other experimental protocols. The 3 mg/kg administered every 3 days induced less sensory cell loss than the other conditions. The findings indicate that 4 consecutive days of 3 mg/kg cisplatin is not a viable ototoxicity model in the Fischer 344/NHsd rat, but that the other models are all effective in inducing comparable cochlear injuries.

Intratympanic Diltiazem-Chitosan Hydrogel as an Otoprotectant Against Cisplatin-Induced Ototoxicity in a Mouse Model

“…30,31 Single dose cisplatin protocols in various animal models demonstrate ABR threshold shifts across all frequencies despite hair cell loss primarily occurring in the basal turn of the cochlea. 24,26,32,33 This suggests that there are other factors beyond the OHCs that contribute to ABR threshold shifts, and that CGP-diltiazem may provide its protective effects at a location outside the organ of Corti.…”

Efficacy and Mechanisms of Antioxidant Compounds and Combinations Thereof against Cisplatin-Induced Hearing Loss in a Rat Model

“…Differences in cochlear anatomy and physiology [98] or in metabolism and pharmacokinetics [98], to name a few, may result in differences in ototoxic response to cisplatin, particularly in the timeline, extent, and pattern of ototoxic damage. For instance, rodents including rats usually require comparatively high doses of cisplatin to affect hearing [99]. This is not necessarily a limitation when searching for basic cellular mechanisms.…”

Experimental animal models of drug-induced sensorineural hearing loss: a narrative review

“…Cisplatin and carboplatin are robust antitumor drugs, but they can also be ototoxic or neurotoxic (55)(56)(57)(58)(59)(60)(61)(62)(63)(64). Cisplatin enters hair cells mainly through copper transport channels to induce oxidative stress, leading to increased reactive oxygen species and inner ear damage (65,66).…”

“…Experiments have indicated that cisplatin mainly injures cochlear hair cells, with OHCs being more susceptible than IHCs; while carboplatin chiefly affects cochlear IHCs, cochlear type I afferent neurons, and vestibular type I hair cells (56,68). Studies demonstrated that a single intraperitoneal dose (commonly 12-16 mg/kg) of cisplatin in rats, mice, or guinea pigs could cause timedependent damage of OHCs and the stria vascularis (Table 2) (56)(57)(58)(59)(60). Some studies also adopted regimens of lower single-dose multiple-administrations which resulted in low mortality rates (69).…”