Ototoxic and nephrotoxic drugs inhibit agonistinduced inositol phosphate formation in rat brain synaptoneurosomes (original) (raw)
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Hearing Research, 1993
The ability of amikacin, neomycin, ethacrynate, mercuric chloride and cisplatin to alter the inositol phosphate (IP) signalling pathway was assessed in the 12-day-old rat cochlea, where the turnover of IPs is coupled to muscarinic receptors. This study was motivated by: (1) the demonstration of neomycin binding to phosphatidylinositol 4,Sbiphosphate, the precursor of IPs, and the fact that ototoxic drugs induce some common symptoms in outer hair cells. At concentrations below 1 mM, none of the compounds changed the control 'H-IP formation. Mercuric chloride, cisplatin and ethacrynate inhibited the carbachol-induced formation of IPs in a dose-dependent manner with IC?,, values of 74, 340 and 430 /LM. respectively. The aminoglycosides
European Journal of Neuroscience, 1993
In the 12-day-old rat cochlea, the synthesis of inositol phosphates (IPs) can be activated via M3 cholinoceptors. This stimulation is blocked by ototoxins (mercury, ethacrynate, cisplatin, neomycin), drugs with side effects that lead to damage of hair cells and strial cells. As these toxic effects can be reversed in vivo by thiol molecules, we investigated whether modifications of thiol compounds could be involved in ototoxin-induced inhibition of the IP turnover in the cochlea. For this purpose, we assessed whether the sulphhydryl-modifying reagents N-ethylmaleimide and cadmium modify the carbachol-stimulated formation of IPs in the 12-day-old rat cochlea. Both molecules inhibit the carbachol effect on a dose-dependent way without altering the basal metabolism of IPs. As cadmium may block some calcium channels, the effect of verapamil, another calcium channel antagonist, was tested. Verapamil (1-50 microM) does not alter carbachol-evoked IP formation, suggesting that the inhibitory effect of cadmium is not due to a calcium influx block. Binding experiments with the muscarinic ligand quinuclidinyl benzylate (QNB) showed that the sulphhydryl-modifying reagents do not displace QNB from binding sites. Combining ototoxins and reagents shows that N-ethylmaleimide acts synergistically with all ototoxins but ethacrynate while cadmium does so only with mercury. Both N-ethylmaleimide and cadmium have additive effects with ethacrynate. As a supplement, disulphide bond-modifying agents do not alter the carbachol-enhanced metabolism of IPs. These results suggest that molecules having thiol-modifying properties inhibit the carbachol-induced turnover of IPs without acting at the muscarinic sites.(ABSTRACT TRUNCATED AT 250 WORDS)
bioRxiv (Cold Spring Harbor Laboratory), 2024
Mechanosensory hair cells of the inner ear are vulnerable to environmental insult, with damage resulting in hearing and balance disorders. Hair cells are sensitive to exposure to toxic agents including therapeutic drugs such as the aminoglycoside antibiotics neomycin and gentamicin. Here we describe distinct mechanisms for aminoglycoside-induced cell death in zebrafish lateral line hair cells. Neomycin exposure results in death from acute exposure with most cells dying within 1 hour of exposure. By contrast exposure to gentamicin results in delayed death, taking up to 24 hours for maximal effect. Washout experiments demonstrate that delayed death does not require continuous exposure, demonstrating two mechanisms where downstream responses differ in their timing. Acute damage is associated with mitochondrial calcium fluxes and can be alleviated by the mitochondriallytargeted antioxidant mitoTEMPO, while delayed death is independent of these factors. Conversely delayed death is associated with lysosomal accumulation and is reduced by altering endolysosomal function, while acute death is not sensitive to these manipulations. These experiments reveal the complexity of responses of hair cells to closely related compounds, suggesting that intervention focusing on early events rather than specific death pathways may be a successful therapeutic strategy.
Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model
Hearing Research, 2004
Cisplatin (CDDP) is a widely used chemotherapeutic agent that is highly ototoxic. Animal studies and clinical trials have shown that thiosulfates can protect against platinum-induced ototoxicity. This study investigated a new model for CDDP ototoxicity in the rat, and tested the potential chemoprotective effect of administering N-acetylcysteine (NAC) before giving CDDP. Long Evans rats were treated with CDDP 6 mg/kg delivered to the aorta via a retrograde right external carotid artery infusion, 15 min after intravenous (IV) infusion of saline (n=8) or NAC 400 mg/kg (n=8), such that the vertebral arteries were perfused. Subsequent groups were similarly treated with NAC 30 min before (n=7) and 4 h after (n=7) CDDP. Auditory brainstem response (ABR) thresholds were tested at 4-20 kHz, 7 days after treatment and compared to baseline ABR values. The NAC-treated rats exhibited no significant change from baseline values at all time intervals, while the saline-treated rats showed marked ototoxicity, especially at higher frequencies. Furthermore, the rats treated with NAC 15 min before CDDP exhibited less overall toxicity to CDDP, as evidenced in weight loss 7 days post-treatment (mean for saline=-39.63 g; mean for NAC=-21.13 g; p=0.0084). These data show that treatment with NAC can prevent CDDP-induced ototoxicity in rats.
The Protective Role of Molsidomine on the Cisplatin-Induced Ototoxicity
Indian Journal of Otolaryngology and Head & Neck Surgery, 2014
This experimental study was designed to investigate the protective effects of molsidomine (MOL) on against cisplatin-induced ototoxicity (CIO). To examine this effect, distortion product otoacoustic emissions (DPOAEs) measurements and serum levels of oxidative and antioxidant status [including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPX), total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI)] were evaluated. Thirty-two female wistar albino rats were divided into four groups including; control (Group K), cisplatin (Group C), cisplatin plus MOL group (Group CM), and MOL group (Group M). DPOAEs measurements between 0.9961 and 8.0003 Hz as DP-gram and input/output (I/O) functions were performed in the same (left) ear of all rats on days 0, 1st, 5th and 12th. Prior to death, the last DPOAEs measurements and blood samples were taken. In the C group, statistically significant DPOAE amplitude reductions were detected at 2.5195, 3.1758, 3.9961, 5.0391, 6.3516 and 8.0039 Hz frequencies (p \ 0.05) between 0th and 1st, 0th and 5th and 0th and 12th days' measurements (p \ 0.05). Serum level of MDA, TAC and OSI levels were significantly higher in the C group versus K group (p \ 0.05). In the CM group, there were no significant differences at all frequencies between 0th and other days' measurements (p [ 0.05) and the serum levels of all biochemical parameters were shifted toward normal values, similar to the K group (p \ 0.05). No significant differences were detected in the either M or K group's measurements. According to these results, cisplatin-related ototoxicity has been significantly prevented by MOL.
Mechanisms of cisplatin-induced ototoxicity and prevention
Hearing research, 2007
Cisplatin is a widely used chemotherapeutic agent to treat malignant disease. Unfortunately, ototoxicity occurs in a large percentage of patients treated with higher dose regimens. In animal studies and in human temporal bone investigations, several areas of the cochlea are damaged, including outer hair cells in the basal turn, spiral ganglion cells and the stria vascularis, resulting in hearing impairment. The mechanisms appear to involve the production of reactive oxygen species (ROS), which can trigger cell death. Approaches to chemoprevention include the administration of antioxidants to protect against ROS at an early stage in the ototoxic pathways and the application of agents that act further downstream in the cell death cascade to prevent apoptosis and hearing loss. This review summarizes recent data that shed new light on the mechanisms of cisplatin ototoxicity and its prevention.
Protection against cisplatin ototoxicity by adenosine agonists
Biochemical Pharmacology, 2004
Cisplatin is a commonly used antineoplastic agent that causes ototoxicity through the formation of reactive oxygen species (ROS). Previous studies have shown that cisplatin causes an upregulation of A 1 adenosine receptor (A 1 AR) in the cochlea, and that application of the adenosine agonist, R-phenylisopropyladenosine (R-PIA), to the round window (RW) results in significant increases in cochlear glutathione peroxidase and superoxide dismutase. These data suggest that adenosine receptors (ARs) are an important part of the cytoprotective system of the cochlea in response to oxidative stress. The purpose of the current study was to investigate the effect of various adenosine agonists on cisplatin ototoxicity using RW application. Auditory brainstem response (ABR) thresholds were recorded in anesthetized chinchillas at 1, 2, 4, 8 and 16 kHz. The auditory bullae were surgically opened, and 1 mM R-PIA, 10 mM 8-cyclopentyl-1,3dipropylxanthine (DPCPX)/R-PIA (1 mM) cocktail, 100 mM 2-chloro-N-cyclopentyladenosine (CCPA), 2-[4-(2-p-carboxy-ethyl)phenylamino]-5 0-N-ethylcarboxamidoadenosine (CGS) or vehicle were applied to the RW. After 90 min, the remaining solution was removed and cisplatin was applied to the RW. The bullae were closed and the animals recovered for 72 h, after which, follow-up ABRs were performed. Cochleae were harvested for scanning electron microscopy (SEM) and for lipid peroxides. Pre-administration of the A 1 AR agonists R-PIA or CCPA significantly reduced cisplatin-induced threshold changes at all but the highest test frequency. In addition, A 1 AR agonists protected against cisplatin-induced hair cell damage and significantly reduced cisplatin-induced lipid peroxidation. Coadministration of the A 1 AR antagonist, DPCPX, completely reversed the protective effects of R-PIA. In contrast, pretreatment with CGS-21680, an A 2A adenosine receptor (A 2A AR) agonist, significantly increased cisplatin-induced threshold changes. Our findings are consistent with the notion that the A 1 AR contributes significantly to cytoprotection in the cochlea, and thereby protects against hearing loss.