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Radioprotective Effect of Aminothiol PrC-210 on Irradiated Inner Ear of Guinea Pig.

ABSTRACT: Radiotherapy of individuals suffering with head & neck or brain tumors subserve the risk of sensorineural hearing loss. Here, we evaluated the protective effect of Aminothiol PrC-210 (3-(methyl-amino)-2-((methylamino)methyl)propane-1-thiol) on the irradiated inner ear of guinea pigs. An intra-peritoneal or intra-tympanic dose of PrC-210 was administered prior to receiving a dose of gamma radiation (3000 cGy) to each ear. Auditory Brainstem Responses (ABRs) were recorded one week and two weeks after the radiation and compared with the sham animal group. ABR thresholds of guinea pigs that received an intra-peritoneal dose of PrC-210 were significantly better compared to the non-treated, control animals at one week post-radiation. Morphologic analysis of the inner ear revealed significant inflammation and degeneration of the spiral ganglion in the irradiated animals not treated with PrC-210. In contrast, when treated with PrC-210 the radiation effect and injury to the spiral ganglion was significantly alleviated. PrC-210 had no apparent cytotoxic effect in vivo and did not affect the morphology or count of cochlear hair cells. These findings suggest that aminothiol PrC-210 attenuated radiation-induced cochlea damage for at least one week and protected hearing.

SUBMITTER: Giese AP

PROVIDER: S-EPMC4657906 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Radioprotective efficacy and toxicity of a new family of aminothiol analogs.

Project description:A family of 17 new nucleophilic-polyamine and aminothiol structures was designed and synthesized to identify new topical or systemic radioprotectors with acceptable mammalian toxicity profiles. design elements included: (i) Length and charge of the DNA-interacting, alkylamine backbone, (ii) nucleophilicity of the reactive oxygen species (ROS)-scavenging group, and (iii) non-toxic drug concentration achievable in animal tissues.Mouse maximum tolerated doses (MTD) were determined by increasing intraperitoneal (IP) doses. To assess radioprotective efficacy, mice received IP 0.5 MTD doses prior to an LD95 radiation dose (8.63 Gy), and survival was monitored. Topically applied aminothiol was also scored for prevention of radiation-induced dermatitis (17.3 Gy to skin).The most radioprotective aminothiols had 4-6 carbons and 1-2 amines, and unlike amifostine and its analogs, displayed a terminal thiol from an alkyl side chain that projected the thiol away from the DNA major groove into the environment surrounding the DNA. The five carbon, single thiol, alkylamine, PrC-210, conferred 100% survival to an otherwise 100% lethal dose of whole-body radiation and achieved 100% prevention of Grade 2-3 radiation dermatitis. By mass spectrometry analysis, the one aminothiol that was tested formed mixed disulfides with cysteine and glutathione.Multiple, highly radioprotective, aminothiol structures, with acceptable systemic toxicities, were identified.

| S-EPMC4358772 | biostudies-literature

Changes in CMDP and DPOAE during acute increased inner ear pressure in the guinea pig.

Project description:During and after an increase of inner ear pressure, induced by injection of artificial perilymph, the 2f1 - f2 and f2 - f1 distortion products (DPs) in cochlear microphonics (CM) and otoacoustic emissions (OAE) were recorded in the guinea pig. An inner pressure increase of approximately 600 Pa gave only small changes in CMDP and DPOAE. Along with a decrease in f1 amplitude, a small decrease in amplitude of the 2f1 - f2 and a small increase in the f2 - f1 were measured in CM. This matches a shift from a symmetrical position of the operating point for hair cell transduction, leading to an increase in even-order distortion and a decrease in odd-order distortion. Similar, a decrease in 2f1 - f2 DPOAE was expected. This might be the case at the generation sites but this effect was then more than compensated for by a better middle ear transfer, accounting for the increase of 0.4 dB of the 2f1 - f2 DPOAE amplitude. In conclusion, changes of overall inner ear fluid pressure have minor effects on cochlear function. This is a relevant finding for further understanding of diseases with changed inner ear fluid volumes, as Ménière's.

| S-EPMC2217622 | biostudies-other

Pharmacokinetics of sodium thiosulfate in Guinea pig perilymph following middle ear application.

Project description:HypothesisTo determine the pharmacokinetics of sodium thiosulfate in the inner ear perilymph following middle ear application in Guinea pigs.BackgroundCisplatin chemotherapy is often associated with a dose-dependent high frequency sensorineural hearing loss. Sodium thiosulfate has been shown to reduce cisplatin-induced ototoxicity when given intravenously, but this may limit the tumoricidal effects of the chemotherapy. Recent animal studies looking at middle ear application of sodium thiosulfate have shown prevention of outer hair cell and hearing loss, but the perilymph pharmacokinetics have not yet been established.MethodsTwenty Guinea pig ears were split into two groups and administered sodium thiosulfate to the middle ear at either a concentration of 250 mg/mL or 50 mg/mL for 30 min. Perilymph samples were then obtained serially through the round window over 6 h. Sodium thiosulfate concentrations were obtained using high-pressure liquid chromatography.ResultsThe 250 mg/mL group had a maximum perilymph concentration of 7.27 mg/mL (±0.83) that decreased to 0.94 mg/mL (±0.03) over 6 h. The 50 mg/mL group had an initial concentration of 1.63 mg/mL (±0.17) and was undetectable after 1 h. The half-life of sodium thiosulfate within perilymph was 0.74 h.Conclusionsand Relevance: The results of this study show that sodium thiosulfate is capable of diffusing through round window and into the inner ear perilymph. Peak levels decline over several hours after exposure. This has a potential application as a localized therapy in the prevention of cisplatin induced ototoxicity.

| S-EPMC6291635 | biostudies-literature

Local Long-Term Inner Ear Drug Delivery in Normal Hearing Guinea Pig-An Animal Model to Develop Preventive Treatment for Noise-Induced Hearing Loss.

Project description:Noise-induced hearing loss (NIHL) is one of the leading causes of sensorineural hearing loss with global importance. The current treatment of choice for patients with hearing problems is a hearing aid or a cochlear implant. However, there is currently no treatment to restore physiological hearing. The development of preventive drugs is currently the focus of hearing research. In order to test the efficacy of a drug, the active ingredient has to be applied at reliable concentrations over a period of time. Osmotic minipumps can provide local drug delivery into the perilymph. Combined with a cochlear implant or a tube, the implantation of the pumps may lead to increased hearing thresholds. Such surgery-related threshold shifts complicate the examination of other factors, such as noise. The aim of the present study was to develop an animal model for the examination of substances that potentially prevent NIHL. For this purpose, six male guinea pigs were unilaterally implanted with a silicon catheter with a hook-shaped microcannula at its tip, attached to an artificial perilymph containing osmotic minipump. One week after surgery, the animals were exposed to four hours of a musical piece, presented at 120 dB SPL, to induce a threshold shift. The implantation of the hook-delivery device caused a moderate threshold shift that allows to detect an additional noise-induced temporary threshold shift. This method enables to investigate drug effects delivered prior to the noise insult in order to establish a preventive strategy against noise-induced temporary threshold shifts. The established drug delivery approach allows the release of drugs into the inner ear in a known concentration and for a known duration. This provides a scientific tool for basic research on drug effects in normal hearing animals.

| S-EPMC9599559 | biostudies-literature

Differential effects of AAV.BDNF and AAV.Ntf3 in the deafened adult guinea pig ear.

Project description:Cochlear hair cell loss results in secondary regression of peripheral auditory fibers (PAFs) and loss of spiral ganglion neurons (SGNs). The performance of cochlear implants (CI) in rehabilitating hearing depends on survival of SGNs. Here we compare the effects of adeno-associated virus vectors with neurotrophin gene inserts, AAV.BDNF and AAV.Ntf3, on guinea pig ears deafened systemically (kanamycin and furosemide) or locally (neomycin). AAV.BDNF or AAV.Ntf3 was delivered to the guinea pig cochlea one week following deafening and ears were assessed morphologically 3 months later. At that time, neurotrophins levels were not significantly elevated in the cochlear fluids, even though in vitro and shorter term in vivo experiments demonstrate robust elevation of neurotrophins with these viral vectors. Nevertheless, animals receiving these vectors exhibited considerable re-growth of PAFs in the basilar membrane area. In systemically deafened animals there was a negative correlation between the presence of differentiated supporting cells and PAFs, suggesting that supporting cells influence the outcome of neurotrophin over-expression aimed at enhancing the cochlear neural substrate. Counts of SGN in Rosenthal's canal indicate that BDNF was more effective than NT-3 in preserving SGNs. The results demonstrate that a transient elevation in neurotrophin levels can sustain the cochlear neural substrate in the long term.

| S-EPMC4649680 | biostudies-literature

Inner ear proteomics/transcriptomics

Project description:The correlation between expression levels of mRNA and protein in mammals is relatively low, with a Pearson correlation coefficient of ~0.40. Post transcriptional regulation contributes to this low correlation. Across taxa, it was demonstrated that translation efficiency, i.e. the protein-to-mRNA ratio in steady state, varies between species in a direction that buffers the protein levels from changes in the transcript abundance. Evidence for this behavior in tissues is sparse. We asked whether this phenomenon is evident in our auditory system data, and on previously obtained proteomic and transcriptomic data from different tissue datasets.

2017-04-24 | PXD003379 | Pride

Inner Ear Tissues

Project description:MPSS analysis of signatures from microdissections of mouse inner ear tissues. Keywords: other

2006-10-01 | GSE4965 | GEO

Protective effect of astaxanthin nanoemulsion on mammalian inner ear hair cells.

Project description:BackgroundAminoglycoside antibiotics are used for treating certain acute infections. However, these drugs cause ototoxicity by inducing inner ear hair cell death.Aims/objectivesWe investigated the protective effect of a nanoemulsion of the carotenoid astaxanthin on mammalian inner ear hair cells against neomycin-induced ototoxicity.Material and methodsDose-response relationship, quantification of hair cell loss, and reactive oxygen species production were assayed in response to neomycin with and without astaxanthin in cultured utricles of CBA/N mice. In addition, auditory brain response (ABR) and hair cell loss after exposure to the nanoformulation and loud noise were examined in vivo in guinea pigs.ResultsAstaxanthin suppressed neomycin-induced reduction of hair cells by reducing the production of hydroxy radicals. Furthermore, hair cell loss in the second rotation of the cochlea was significantly lower in the astaxanthin group than in the noise-only group.Conclusions and significanceThe blood-labyrinth barrier limits the successful delivery of drugs for inner ear complications. However, in the nanoemulsion form, astaxanthin can penetrate the round window (fenestra ovale) membrane, enabling topical administration. Thus, astaxanthin nanoemulsion could be useful in treating ototoxicity in individuals with inner ear complications.

| S-EPMC10494832 | biostudies-literature

Comparison of the Pathway to the Inner Ear Between Postauricular and Intramuscular Injection of Dexamethasone in Guinea Pigs.

Project description:BackgroundPostauricular injection as a local therapy has been confirmed to be effective for inner ear diseases. However, the mechanism for the drugs entering the inner ears remains unknown. This study aims to compare the distribution of dexamethasone by intramuscular injection with that by postauricular injection, and explore the pathway of the drugs entering the inner ears.MethodsAn in vivo optical imaging system was used to conduct a time course observation to compare the distribution of dexamethasone by intramuscular injection with that by postauricular injection in male guinea pigs. The drug availability in the tympanic mucosa, tympanum, endolymphatic sac, and cochlea was observed by a confocal laser scanning microscope.ResultsThe local fluorescent intensity by postauricular injection was significantly higher in the inner ears, and lower in partial peripheral organs, than that by the intramuscular injection. The drug metabolism by postauricular injection exhibited an obviously sustained release effect in the inner ears. Drugs by postauricular injection might enter the endolymphatic sac through the posterior auricular artery and occipital artery, as well as the connections of the mastoid emissary vein, sigmoid sinus and endolymphatic sac.ConclusionMore drugs concentrated in the inner ear for longer therapeutic time and less systemic delivery implied more effective and less risk of side effects through postauricular injection than intramuscular injection safer for the treatment of inner ear diseases.

| S-EPMC8930822 | biostudies-literature

Inner ear expression data from pooled inner ear tissue from stages 56,57,58 Xenopus laevis larval inner ears

Project description:The inner ear continues to grow and develop until the auditory and vestibular systems reach full maturity and all of the genes involved in this process have yet to be identified. Previous gene based analysis have primarily focused on the early developmental stages following induction and initial formation of the inner ear. The aim of this study is to identify new candidate genes for inner ear development. Microarrays were used to produce expression profiles from larval stages 56,57,58 of the Xenopus laevis inner ear. The data produced from this work represent an annotated resource that can be utilized by the Xenopus community to provide candidates for further functional analysis. Xenopus inner ears were isolated from larval animals for RNA extraction and hybridization to Affymetrix GeneChip microarrays.

2016-02-29 | E-GEOD-73829 | biostudies-arrayexpress

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