Round window pH manipulation alters the ototoxicity of systemic cisplatin

The effect of manipulation of pH on the ototoxicity of systemic cisplatin was studied in Wistar rats. After control auditory brainstem responses (ABR) were performed, the auditory bullae were opened and acidic (pH 6.0), neutral (pH 7.4) or basic (pH 9.0) phosphate-buffered saline (PBS) was applied to fill the round window niche (RWN). After 30 min, 13 mg/kg cisplatin solution or saline was administered intraperitoneally. After 3 days, follow-up ABRs were performed and cochleae were processed for morphological analysis. Animals that received basic PBS on the RWN and cisplatin intraperitoneally had significantly smaller ABR threshold shifts compared to rats pretreated with neutral pH buffer (P<0.05). Animals that received acidic PBS on the RWN and systemic cisplatin showed significantly greater ABR threshold shifts compared to those pretreated with neutral pH buffer (P<0.05). No significant threshold changes were observed in animals that received buffer of any pH on the RWN, followed by saline intraperitoneally. Semiquantitative analysis of hair cell survival confirmed a protective effect by basic PBS against cisplatin and a synergistic effect by acidic PBS on cisplatin ototoxicity (P<0.05). It appears that changes in cochlear pH can modulate the ototoxic effects of systemically applied cisplatin.     

Experimental study on ototoxicity of cisplatin

The ototoxicity of cisplatin and a comparison of the ototoxicity between cisplatin and kanamycin had been studied by morphological and biochemical methods. The results showed that the ototoxic effects of both drugs were similar, mainly affecting the cochlea, and next the vestibule. Lesions developed from the periphery to the center. The stria vascularis, the spiral ligament and the secretory epithelium of the vestibule were slightly injured by cis-platin. The K+ and Na+ concentrations of cochlear perilymph changed after the administration of both drugs. The ototoxicity of cis-platin appeared to be accumulated. So, while using cisplatin clinically, we stress the need for careful monitoring of the cochlear and vestibular functions.     

Hyaluronan applied to lesioned round window membrane is free from cochlear ototoxicity

Hyaluronan (HYA) in 1% solution was instilled into the round window (RW) niche of rats (n = 6) prior to perforating the round window membrane (RWM). Cochlear functioning and structure were then monitored by recording auditory brainstem responses (ABRs) at 2-31.5 kHz and by scanning electron microscopy. Perforation of the RWM alone (n = 6) resulted in immediate loss of ABR thresholds between 6 and 31.5 kHz in 2 of 6 animals. Similar results were obtained after instilling HYA into the RW niche and subsequent RWM perforation (n = 6). After 2 months, ABR thresholds were recorded at all frequencies in the HYA-treated animals, whereas in 2 of the controls no ABR thresholds could be elicited at 20 and 31.5 kHz. However, in both treatment groups the mean ABR thresholds and mean latencies for wave II at the ABR threshold returned to the pre-surgical (normal) range after 2 months. With respect to the cochlear morphology the results in both treatment groups were also alike including minor structural changes in hair cell stereociliae but no loss of hair cells. It is concluded that HYA, when instilled into the middle ear with the inner ear opened, is free from cochlear otoxicity.     

Clinical study on the ototoxicity of cisplatin with distortion products

Distortion products are an objective method of hearing assessment that provides a rapid way to evaluate the functional status of the cochlea, so they are interesting for monitoring drug ototoxicity. We studied 50 ears from patients who received an ototoxic drug, cisplatin. Two consecutive measurements were made using distortion products 2f1-f2, before and after taking the ototoxic agent. We observed a significant reduction in the amplitudes of the DP-grams. At the same time, we evaluated the influence of previous sensorineural hearing loss on DP-grams, dividing the patients into two groups: normal hearing and sensorineural hearing loss. All these patients were evaluated at the same time by conventional audiometry in order to compare the effect of cisplatin on both tests. We conclude that cisplatin produced little effect on audiometric thresholds and an evident effect on the amplitude of distortion products.     

The round window membrane following application of staphylococcal exotoxin: An electron microscopic study

The round window membrane has been considered as a pathway for the passage of toxic substances from the middle ear cavity to the vestibular labyrinth in cases of otitis media. To determine the role of the round window membrane in this passage, chinchillas were given intrabullar inoculations with staphylococcal exotoxin and the round window membranes were examined electron microscopically. We observed cytoplasmic vacuolization, intercellular edema, cellular and nuclear swelling of the surface epithelia and polymorphonuclear leukocyte (PMN) infiltration of the fibrous layer. Light microscopic observation of the labyrinth revealed PMN infiltration of the most basal portion of the scala tympani. These findings demonstrate a chemotactic effect of the toxin for PMNs and support the concept of the round window membrane as an important avenue of entry.     

Anomaly of the round window a histopathological study using a graphic reconstruction method

Although literature to date has reported that anomalies of the round window occur infrequently, no study to our knowledge has investigated such anomalies quantitatively. Thus, we developed a graphic reconstruction method and used it to study histology sections of the temporal bones. By this method we studied quantitatively the morphology of the round window of individuals with Mondini dysplasia of the inner ear and compared it to that of individuals with no anomaly. Iit was found that in 3 of 19 individuals with dysplasia, the total area of the round window was more than two standard deviations below the mean, thus small enough to be called anomalous. Moreover, the area of the round window was statistically significantly smaller in the ears from individuals with Mondini dysplasia, as a group, than in normal ears. This round window anomaly seems to be due to interruption of the normal development of the round window early in fetal life, as the result of poor development of the cartilage bar between the tympanic cavity and the subarachnoid space and also of the otic capsule in the hook portion of the basal turn of the cochlea.     

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.     

Surgery of the round window

Tympanotomy is routinely performed in our institution to control the round window membrane for patients with recurrent sudden deafness, with Meniere-like attacks, and those with Meniere's disease. In a large number of these patients, especially those with vertigo, perilymph fistula has been diagnosed. Most patients are free of attacks after the fistula has been closed, and in those with a short history of illness, hearing can become normal. In the future, closure of the round window membrane should be considered an important procedure in the treatment of inner ear dysfunctions.     

Immunodefense of the round window

A systematic analysis using serial sectioning of the round window membrane (RWM) in the cynomolgus monkey was performed. Light and transmission electron microscopy (LM and TEM) revealed that the RWM rim may be endowed with gland-like structures with glyco-protein material secernated into the window niche. This was detected in one third of the specimens. The secreted material displayed waste material and scavenger cells. There was also a rich network of capillaries, lymph channels, and sinusoidal veins containing leukocytes. Their abluminal surfaces displayed mature plasma cells and monocytes. These findings suggest that in certain primates the middle ear may have developed specific immunoprotective means for disposal of foreign and noxious substances before they reach the inner ear.     

L-NAME 对顺铂耳毒性影响的实验研究

目的本研究旨在通过建立顺铂内耳中毒的动物模型,探索一氧化氮合酶(NOS)在顺铂的耳毒性机制中的影响,为临床预防和治疗顺铂的耳毒性提供理论依据.方法将豚鼠随机分成三组.对照组给予生理盐水;试验组给予顺铂;拮抗组预先给予N-硝基-L-甲基-精氨酸(L-NAME)后再给顺铂.对耳蜗的iNOS的活性进行免疫组化的研究,对L-NAME对顺铂的耳蜗损害所起的作用进行扫描电镜观察.结果光镜下,对照组螺旋器的结构正常,呈iNOS阴性染色;试验组的内、外毛细胞明显变性,呈iNOS阳性染色.扫描电镜下,对照组内、外毛细胞的纤毛排列整齐;试验组的绝大部分内、外毛细胞的纤毛散乱,倒伏,甚至消失;拮抗组的大多数内、外毛细胞的纤毛排列整齐,少数可见纤毛融合或消失.结论一氧化氮(NO)在顺铂的内耳毒性作用机制中发挥着重要的作用,应用NOS的拮抗剂可以减轻其内耳毒性.     

Cochlear structure and function after round window application of ototoxins

Topical round window application of ototoxic agents has been a useful method for studying ototoxicity and hearing loss in the mammalian cochlea. For example, species-specific differences in cochlear susceptibility to damage have been documented using this technique. Carboplatin has been characterized in the literature as a selective inner hair cell (IHC) toxin in chinchillas, while cisplatin has been characterized as a selective outer hair cell (OHC) toxin. The present experiment quantified dose-dependent damage to cochlear hair cells in the chinchilla after a single direct round window application of either cisplatin or carboplatin. Detailed cytocochleograms were obtained for the entire cochlear duct, for a range of doses, along with auditory brainstem response thresholds. In agreement with the literature, although there was variability, at the lowest concentrations tested (2 and 3 mg/ml), carboplatin produced substantial IHC damage with no OHC damage. In contrast, the effects of cisplatin were more variable, and contrary to published reports, across the range of doses producing OHC damage, IHC damage was always observed. Limitations of direct round window ototoxin treatments are discussed, in addition to their potential application in the study of tinnitus.     

Effect of oral magnesium supplementation on cisplatin ototoxicity

OBJECTIVE: The purpose of this study is to evaluate the effect of Mg supplementation on cisplatin ototoxicity in guinea pigs. METHODS: Twenty guinea pigs were divided into two groups and were fed different Mg-containing diets. Following 6 mg/kg of cisplatin injection, the animals were sacrificed and the extent of cochlear damage was assessed with the scanning electron microscope and compared with the control group. Additionally, intracardiac blood samples were taken to determine the plasma Mg levels of the subjects before and after cisplatin exposure. RESULTS: The outer hair cell damage owing to cisplatin was not statistically different in both groups (p > .05). Following cisplatin injection, the plasma Mg levels of both groups were found to be significantly lower than the plasma Mg levels before exposure, but the resulting values of the Mg-rich fed group was compatible with control group Mg levels. CONCLUSION: Our study showed that a Mg-rich diet can prevent the severe hypomagnesemia that cisplatin causes in guinea pigs, but this measure has not been enough to protect the inner ear against its ototoxic effect.     

The effect of resveratrol on the prevention of cisplatin ototoxicity

One of the most important adverse effects of cisplatin, a chemotherapeutic agent which is widely used in the treatment of cancer patients, is hearing loss. This has primarily been associated with the loss of inner ear hairy and spiral ganglion cells due to oxidative stress. Resveratrol is known to be an antioxidant agent, which has the theoretical potential of preventing cisplatin-related ototoxicity. This experimental study was approved by Animal Ethics Committee of Inonu University (2008–20) and supported by Inonu University Scientific Research Projects Support Fund (2009–17). Thirty-four 3-month-old Wistar albino female rats weighing 210–270?g were used in the study. The animals were allocated into four groups: in cisplatin group (Group A), a single dose of 12?mg/kg cisplatin was administered intraperitoneally to 10 rats; in cisplatin?+?resveratrol group (Group B), a single dose of 12?mg/kg cisplatin and 10?mg/kg resveratrol were administered intraperitoneally for 5?days to 10 rats; in resveratrol group (Group C), 10?mg/kg resveratrol was administered intraperitoneally for 5?days to seven rats and in control group (Group D), resveratrol solvent (5% alcohol–95% physiological saline) was administered intraperitoneally for 5?days to seven rats. Resveratrol administration has begun 1?day before cisplatin administration in the group treated with cisplatin and resveratrol combination. Distortion product otoacoustic emission (DPOAE) (Grason Stadler, Madison, USA) measurements were performed in the same ear of all rats (right ear) under general anesthesia at baseline, 1st and 5th days after drug administration. Statistically significant distortion product amplitude reductions were found in the cisplatin group at 1,418, 2,003, 3,363, 5,660, 8,003 and 9,515?Hz frequencies. Whereas in the cisplatin?+?resveratrol group, statistically significant difference was found between 1st and 5th day measurements only at 3,996?Hz frequency. No significant differences were noted between the measurements either in the resveratrol or in the control groups. According to these results, cisplatin-related ototoxicity has been greatly prevented by resveratrol use.