Cisplatin-induced Ototoxicity In Guinea Pigs Research Articles

Optimal N-acetylcysteine concentration for intratympanic injection to prevent cisplatin-induced ototoxicity in guinea pigs

Background Cisplatin is a chemotherapy drug that can induce sensorineural hearing loss. At present, no otoprotective agent is approved for use. Objectives This study investigated the optimal concentration of intratympanic N-acetylcysteine (NAC) to prevent cisplatin-induced ototoxicity in a guinea pig model. Materials and methods Guinea pigs (n = 64) were treated with a single intratympanic injection containing different NAC concentrations or saline (control) 3 days prior to intraperitoneal injection with cisplatin. The threshold change in the auditory brainstem response was assessed. Results Four weeks after intraperitoneal cisplatin injection, only the group that received 2% NAC exhibited significant otoprotection (p < .05) compared with the control. Otoprotection was observed at all the frequencies tested (1k, 2k, 4k, and 8k Hz). The 2% NAC group also exhibited significant otoprotection (p < .05) compared with the other NAC groups (at 1k, 2k, 4k, and 8k Hz). The 4% NAC group exhibited significantly reduced hearing capacity (p < .05) in the fourth week compared with controls. Conclusions and significance Intratympanic NAC administration is an efficient and safe means of preventing cisplatin-induced ototoxicity. In our animal model, the optimal intratympanic NAC concentration was 2%; concentrations of 4% loss of otoprotection.

The Effects of Riluzole on Cisplatin-induced Ototoxicity.

Introduction Riluzole (2-amino-6-trifluoromethoxy benzothiazole) is known as a neuroprotective, antioxidant, antiapoptotic agent. It may have beneficial effects on neuronal cell death due to cisplatin-induced ototoxicity. Objective To evaluate the effect of riluzole on cisplatin-induced ototoxicity in guinea pigs. Methods Twenty-four guinea pigs, studied in three groups, underwent auditory brainstem response evaluation using click and 8 kHz tone burst stimuli. Subsequently, 5 mg/kg of cisplatin were administered to all animals for 3 days intraperitoneally (i.p.) to induce ototoxicity. Half an hour prior to cisplatin, groups 1, 2 and 3 received 2 ml of saline i.p., 6 mg/kg of riluzole hydrochloride i.p., and 8 mg/kg of riluzole hydrochloride i.p., respectively, for 3 days. The auditory brainstem responses were repeated 24 hours after the last drug administration. The cochleae were analyzed by transmission electron microscopy (TEM). Results After drug administiration, for 8,000 Hz stimulus, group 1 had significantly higher threshold shifts when compared with groups 2 ( p < 0.05) and 3 ( p < 0.05), and there was no significant difference in threshold shifts between groups 2 and 3 ( p > 0.05). Transmission electron microscopy findings demonstrated the protective effect of riluzole on the hair cells and the stria vascularis, especially in the group treated with 8 mg/kg of riluzole hydrochloride. Conclusion We can say that riluzole may have a protective effect on cisplatin- induced ototoxicity. However, additional studies are needed to confirm these results and the mechanisms of action of riluzole.

Effect of Hippophae rhamnoides extract on Cisplatin-induced ototoxicity in Guinea Pigs

No previous studies have examined the effect of Hippophae rhamnoides fruit extract (HRE), which contains both water and fat soluble vitamins, on cisplatin-induced ototoxicity. Therefore, the aim of the study was to investigate the effects of HRE on cisplatin-induced ototoxicity in Guinea pigs and to evaluate the biochemical, gene expression and histopathological changes associated with cisplatin use. Experimental animals were divided into three groups: healthy (HG), HRE+cisplatin (HRC) and cisplatin control (CCG) groups. Biochemical, gene expression and histopathological examinations were carried on the removed inner ear tissues. In the HRC group, the oxidant parameter was lower and the anti-oxidant parameter was higher than in the CCG. These results are supported by gene expression levels and histopathological results. The use of HRE against cisplatin-induced oxidative ototoxicity may be easier, more cost effective and more beneficial than the use of vitamins alone or in combination with each other.

Evaluation of the protective effect of α-lipoic acid on cisplatin ototoxicity using distortion-product otoacoustic emission measurements: an experimental animal study.

The aim of our study was to determine the effectiveness of intratympanic α-lipoic acid injection as an otoprotective agent against cisplatin-induced ototoxicity in guinea pigs. Twenty-four adult male albino guinea pigs with normal hearing were divided into 4 groups. The guinea pigs received intraperitoneal cisplatin in group 1, intraperitoneal cisplatin and intratympanic α-lipoic acid in group 2, intratympanic α-lipoic acid in group 3, as well as intraperitoneal cisplatin and intratympanic saline in group 4. Distortion-product otoacoustic emission measurements were obtained for both ears at the following time points: before administration (baseline recording) and on day 3 (72 h later). In group 1 (cisplatin), significant deterioration was observed at all frequencies on day 3 (P < 0.05). In group 2 (cisplatin + α-lipoic acid), deterioration was observed at all frequencies on day 3; however, this deterioration did not reach a statistical significance (P > 0.05). In group 3 (α-lipoic acid), no significant difference was observed between baseline and day 3 (P > 0.05). In group 4 (cisplatin + saline), deterioration was observed at all frequencies on day 3; however, this deterioration did not reach a statistical significance (P > 0.05). Cisplatin-induced hearing loss in the guinea pigs may be limited to some extent by the concomitant use of α-lipoic acid. Dose-dependent changes in the possible effects of α-lipoic acid need further investigation. Future morphologic studies may contribute to expose clearly the protective effect of α-lipoic acid.

New Diagnostic and Therapeutic Approaches in Otologic Diseases

Cochlear pathologies and vestibular disorders have been investigated in detail in the recent years. Recent advances in diagnostic and therapeutic methods have introduced new investigations about the cytologic degenerations and regenerations of cochlear cells. Knowledge and understanding of otologic diseases have led to the development of novel therapies, approaches, and/or tools. This special issue covers the important topics in the diagnosis and therapies of otologic diseases including chronic otitis media, tinnitus, ototoxicity, and hearing loss. Investigation of the Presence of Biofilms in Chronic Suppurative Otitis Media, Nonsuppurative Otitis Media, and Chronic Otitis Media with Cholesteatoma by Scanning Electron Microscopy. Biofilms have been shown to play a major role in the pathogenesis of otolaryngologic infections. However, very limited studies have been undertaken to demonstrate the presence of biofilms in tissues from patients with chronic otitis media (COM) with or without cholesteatoma. E. Kaya et al. found that their study supports the hypothesis that biofilms are involved in chronic suppurative otitis media, cholesteatoma, and to a lesser degree, chronic nonsuppurative otitis media. The presence of biofilms was significantly higher in the middle ear mucosa compared with the mastoid and ossicle samples. They emphasized that careful use of topical or systemic antimicrobials is essential and during surgery, hypertrophic tissue must be carefully removed from normal tissue. Is It Necessary to Do Temporal Bone Computed Tomography of the Internal Auditory Canal in Tinnitus with Normal Hearing? Tinnitus is the perception of sound without an external stimulus. The prevalence of tinnitus varies between 3–30% of all population. As we know very well, tinnitus can be seen due to the pressure of the acoustic neuromas, cerebellopontine angle tumors, and vascular lesions, such as vascular loop to the eight cranial nerve reported in the literature. The development of the tinnitus can be observed due to nerve edema, degeneration, and compression in the canal. Accordingly, the pathological conditions that affect the width of the canal can lead to tinnitus due to compression. T. L. Kumral et al. investigated the diameter of internal acoustic canal in physiologically impaired tinnitus patients as the etiology may be due to anatomical differences of the temporal bone. In conclusion they found that there were no anatomical differences in the etiology of tinnitus rather than physiological degeneration in the nerves. Efficacy of Low-Level Laser Therapy in the Management of Tinnitus due to Noise-Induced Hearing Loss: A Double-Blind Randomized Clinical. Several remedial modalities for the treatment of tinnitus have been proposed, but an effective standard treatment is still to be confirmed. In the present study, A. Mollasadeghi et al. investigate the effect of low-level laser therapy on tinnitus accompanied by noise-induced hearing loss. They found low-level laser therapy to be effective in alleviating tinnitus in patients with noise-induced hearing loss, although this effect has faded after 3 months of follow-up. The Role of Thiamine Pyrophosphate in Prevention of Cisplatin Ototoxicity in an Animal Model. Cisplatin ototoxicity has several characteristics. Inner ear toxicity is often a dose limiting side effect that hampers optimal cisplatin-based chemotherapy. It is normally manifested as a sensorineural hearing loss beginning in the high frequencies, successively progressing towards the speech frequency range. O. Kuduban et al. investigate the effectiveness of thiamine pyrophosphate against cisplatin-induced ototoxicity in guinea pigs. They found that systemic administration of thiamine pyrophosphate yielded statistically significant protection to the cochlea of guinea pigs from cisplatin toxicity. They emphasized that further experimental animal studies are essential to determine the appropriate indications and dosages of thiamine pyrophosphate before clinical use. Extended High Frequency Audiometry in Polycystic Ovary Syndrome. Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder affecting 5–10% of women in the reproductive age. Disease is characterized by oligo/amenorrhea, hyperandrogenism, and polycystic ovaries. PCOS is a chronic proinflammatory state. C. Kucur et al. evaluated extended high frequency hearing loss in PCOS patients. They concluded that PCOS patients have hearing impairment especially in extended high frequencies. Further studies are needed to help elucidate the mechanism behind hearing impairment in association with PCOS and to see whether the impairment of extended high frequency audiometry in these cases is progressive. Possible Protective Effect of Sertraline against Cisplatin-Induced Ototoxicity: An Experimental Study. Cisplatin is a widely used chemotherapeutic agent but its ototoxicity side effect can occur in the majority of patients. Lots of agents were tried to prevent this, but there is not a routine treatment modality yet. The aim of this study was to evaluate the otoprotective effect of sertraline, which is an antidepressant with neuroprotective effects, against cisplatin, in rats. M. Ozturk et al. showed that sertraline seems to have a protective effect on cisplatin ototoxicity, and could be used to prevent the ototoxicity and also to treat the depression that occurred in cancer patients together. Fatih Oghan Cemal Cingi Erkan Karatas Sebahattin Cureoglu

Prevention of cisplatin ototoxicity: Efficacy of micronized flavonoid fraction in a guinea pig model

ObjectiveTo evaluate the effectiveness of micronized flavonoid fraction in preventing cisplatin ototoxicity in a guinea pig model. MethodsThis study was conducted on 23 guinea pigs in the Animal Laboratory of Izmir Atatürk Training and Research Hospital. Animals were divided into three groups: Group 1 consisted of eight animals receiving cisplatin only; Group 2 contained eight animals receiving cisplatin+micronized flavonoid fraction; and Group 3 contained seven animals that received micronized flavonoid fraction only. Their cochlear reserve was evaluated by measuring the distortion product otoacoustic emission on days 0 and 7. ResultsIn Groups 1 and 2, the intragroup signal–noise ratios were statistically different at all frequencies tested (based on negative ranks, p<0.05). In Group 3, the intragroup signal–noise ratios did not differ significantly at the frequencies tested (p>0.05). Comparison of the three groups showed statistically significant differences among the groups (p<0.05). The post hoc Bonferroni correction showed statistically significant differences among all three groups (p<0.016). The median signal–noise ratio of the three groups tended to increase (z-value was positive for all the frequencies tested; p<0.01). ConclusionMicronized flavonoid fraction (Daflon) is effective against cisplatin-induced ototoxicity in guinea pigs.

Protective role of resveratrol against cisplatin induced ototoxicity in guinea pigs

ObjectiveThe aim of this study was to evaluate the effectiveness of systemic administration of resveratrol against cisplatin-induced ototoxicity in guinea pigs. Materials and methodsHealthy guinea pigs (n=24) were randomly divided into four groups. Group 1 (n=6) received resveratrol+cisplatin, group 2 (n=6) received 4% ethanol+cisplatin, group 3 (n=6) received cisplatin, and group 4 (n=6) received saline. Cisplatin was administered at a dose of 10mg/kg/day on days 14 and 15 of the study. Resveratrol (10mg/kg/day), 4% ethanol, and saline were administered throughout the study. Baseline auditory brainstem responses (ABR) (4kHz, 8kHz, and click stimulus) were determined for all groups. ABR was repeated 72h after the last dose of cisplatin in order to record the threshold shifts. The ABR threshold shifts for the click stimulus, 4-kHz- and 8-kHz-frequency stimuli were compared after drug administration. After follow-up ABRs the animals sacrificed under deep sedation and their cochleae were removed. Left cochleae were immediately harvested for measurement of level of reactive oxygen species (ROS). Right cochleae were prepared for histological changes which were observed by scanning electron microscopy (SEM). ResultsFor the all stimulus, there was a significant threshold difference among the groups (p<0.01). Group 3 had a significantly higher threshold shift at all stimuli when compared with groups 1 and 4. There was no significant threshold shifts in all stimuli between groups 2 and 3. The resveratrol-treated group 1 showed preservation of threshold in ABR (p≤0.05). SEM showed that inner and outer hair cells were preserved in the group 1. Level of reactive oxygen species (ROS) were significantly higher in groups 2 and 3 compared with groups 1 and 4 (p≤0.05). ConclusionThese results indicated that systemic administration of resveratrol afforded statistically significant protection to the cochlea of guinea pigs from cisplatin toxicity. Experimental dose of resveratrol injections may have a protective effect against cisplatin ototoxicity in guinea pigs.

Protective effects of Salvia miltiorrhiza against cisplatin-induced ototoxicity in guinea pigs

Objective The aim of the study was to investigate the protective effects of Salvia miltiorrhiza (SM) against cisplatin-induced ototoxicity in guinea pigs. Methods Thirty-nine guinea pigs were randomly divided into 3 groups. The first group (control group) received physiologic saline by intraperitoneal (i.p.) injection for 5 days. The second group (cisplatin group) was treated with cisplatin (2 mg/kg per day, i.p. injection) for 5 days. The third group (SM group) was given SM (8 g/kg per day, i.p. injection) for 2 days and then was given SM (8 g/kg per day, i.p. injection) and cisplatin (2 mg/kg per day, i.p. injection) for 5 days. Auditory brain stem response (ABR) and cochlea blood flow measurement were used to evaluate cochlea function. The structures of cochlea were observed by light microscope, scanning electron microscope, transmission electron microscope (TEM), and immunohistochemical examination. Results Cisplatin could cause severe acoustic damages including significant elevation of ABR threshold, substantial losses of outer hair cells and inner hair cells, and severe damage on the stria vascularis and spiral ganglion cells (SGCs). Although in SM group, the increased tendency of threshold was milder than that in cisplatin group. The damages in cochlea and stria vascularis were also less severe than those in cisplatin group. The expression of induced nitric oxide synthase in the cochlea and SGC in SM group was lower than that in cisplatin group. Conclusions Salvia miltiorrhiza can significantly reduce the cisplatin-induced side effects.

The protective effect of intratympanic dexamethasone on cisplatin-induced ototoxicity in guinea pigs

The purpose of this study was to investigate the effectiveness of intratympanic dexamethasone injection as a protection agent against cisplatin-induced ototoxicity. The four groups of guinea pigs were injected as follows: 1) cisplatin, 2) intratympanic dexamethasone, 3) cisplatin following intratympanic dexamethasone, and 4) cisplatin after intratympanic saline. Before and 3 days following injections, the ototoxic effect was measured with distortion product otoacoustic emissions (DPOAEs). The DPOAEs amplitudes and signal-to-noise ratio (SNR) values at 1 to 6 kHz frequencies for group 1 animals after injections significantly decreased over those before injections (P < 0.05). In group 2, there were no significant differences in DPOAE amplitude and SNR values between before and after intratympanic dexamethasone injections (P > 0.05). Considering group 3, there were also no significant differences in DPOAEs amplitudes and SNR values before and after of dexamethasone and cisplatin injections (P > 0.05). Intratympanic dexamethasone injection did not cause any ototoxic effect; in contrast, it might have a significant protective effect after cisplatin injection.

Acceleration of cisplatin ototoxicity by perilymphatic application of 4-methylthiobenzoic acid

The antitumor agent cisplatin has dose-limiting side effects such as ototoxicity. Systemical co-treatment with anti-oxidants like 4-methylthiobenzoic acid (MTBA) and sodium thiosulfate (STS) provides protection against cisplatin ototoxicity. However, systemically administered protective agents may reduce the chemotherapeutic effect of cisplatin. Local application of the protective agents could avoid this undesirable effect. In the present study, we aimed at suppressing cisplatin-induced ototoxicity in guinea pigs by administering MTBA or STS perilymphatically through cochlear perfusion. Guinea pig cochleas were perfused for 10 min with artificial perilymph (ArtP) containing cisplatin at 0.3 mg/ml, either alone, or in combination with MTBA (0.1 or 1.0 mg/ml) or STS (0.75 or 3.0 mg/ml). The compound action potential (CAP) and the summating potential (SP), evoked by 8 kHz tone bursts, and the endocochlear potential (EP; MTBA only) were measured just before and 1, 2, 3 and 4 h after perfusion. Cisplatin gradually reduced the CAP amplitude in time. Adding MTBA only accelerated this ototoxic effect. After cisplatin treatment a decline was found in the EP, irrespective of co-treatment, i.e., addition of MTBA did not accelerate the EP decrease. In contrast to MTBA, STS ameliorated the ototoxic effect of cisplatin. In conclusion, local application of anti-oxidants can ameliorate cisplatin ototoxicity but this is not a feature of all anti-oxidants.

Effects of trolox, locally applied on round windows, on cisplatin-induced ototoxicity in guinea pigs

Objective: Cisplatin (CDDP), an antitumor agent widely used in the treatment of pediatric solid tumors, has dose-limiting side effects such as ototoxicity and nephrotoxicity. Recently, evidence has been accumulated to demonstrate that these side effects are closely related to oxidative stress. In the present study, we attempted to suppress CDDP-induced ototoxicity in guinea pigs by administering trolox, a water-soluble analogue of α-tocopherol which is a natural lipid-soluble antioxidant, locally on round windows. Methods: Hartley albino guinea pigs (250–300 g) were treated with CDDP (0.3 mg/ml) in the presence or absence of a combined treatment of trolox (5 mM). Both drugs were administered locally on round windows. Results: The combined treatment of trolox distinctly improved the ototoxic side effects induced by CDDP. These were: elevation of auditory brain stem response threshold at 4, 8 and 16 kHz and substantial losses of outer hair cells with the base-to-apex gradient. Conclusion: Trolox, locally applied on round windows, showed a suppression on CDDP-ototoxicity. The results obtained in the present study suggest that a local application of trolox in the tympanic cavity can be a promising candidate to prevent the CDDP-ototoxicity in the future.

Effects of α-tocopherol on cisplatin-induced ototoxicity in guinea pigs

Cisplatin (CDDP), an antitumor agent widely used in the treatment of head and neck cancers, has dose-limiting side effects such as ototoxicity and nephrotoxicity. Recently, evidence has been accumulated to demonstrate that these side effects are closely related to oxidative stress. In the present study, we attempted to suppress CDDP-induced ototoxicity and nephrotoxicity in guinea pigs by administering α-tocopherol, a naturally occurring antioxidant. Hartley albino guinea pigs (250∼300 g) were treated with CDDP (4 mg/kg intraperitoneally (I.P.)) for 3 days in the presence and absence of α-tocopherol (50 mg/kg I.P.) injection for 6 days. The combined treatment of animals with α-tocopherol distinctly improved the CDDP-induced side effects. These were: loss of Preyer’s reflex at high frequencies; distinct elevation of auditory brain stem response threshold at 16 kHz; increased lipid peroxidation in the cochlea determined by the malondialdehyde–thiobarbituric acid method; substantial losses of outer hair cells in the basal and second turns of the cochlea; fragmentation of nuclear DNA detected by the TUNEL method in cochlear hair cells and cells in the stria vascularis; and increases in serum BUN and Cr. These results strongly suggest that α-tocopherol suppresses CDDP-induced ototoxicity and nephrotoxicity via the suppression of the increased production of reactive oxygen species.