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Patients undergoing cochlear implantation could benefit from a simultaneous application of drugs into the ear, helping preserve residual low-frequency hearing and afferent nerve fiber populations. One way to apply drugs is to incorporate a cannula into the implant, through which drug solution is driven. For such an approach, perilymph concentrations achieved and the distribution in the ear over time have not previously been documented. We used FITC-labeled dextran as a marker, delivering it into perilymph of guinea pigs at 10 or 100 nL/min though a cannula incorporated into a cochlear implant with the outlet in the mid basal turn. After injections of varying duration (2 hours, 1 day or 7 days) perilymph was collected from the cochlear apex using a sequential sampling technique, allowing dextran levels and gradients along scala tympani to be quantified. Data were interpreted quantitatively using computer simulations of the experiments. For injections of 2 hours duration, dextran levels were critically influenced by the presence or absence of fluid leakage at the cochleostomy site. When the cochleostomy was fluid-tight, substantially higher perilymph levels were achieved at the injection site, with concentration declining along scala tympani towards the apex. Contrary to expectations, large dextran gradients along scala tympani persisted after 24 hours of sustained injection and were still present in some animals after 7 days injection. Functional changes associated with implantation and dextran delivery, and the histological state of the implant and cannula were also documented. The persistent longitudinal gradients of dextan along the ear were not readily explained by computer simulations of the experiments based on prior pharmacokinetic data. One explanation is that inner ear pharmacokinetics are altered in the period after cochlear implantation, possibly by a permeabilization of the blood-labyrinth barrier as part of the immune response to the implant. [ABSTRACT FROM AUTHOR]

There are a variety of techniques available to investigate endolymph dynamics, primarily seeking to understand the cause of endolymphatic hydrops. Here we have taken the novel approach of injecting, via a glass micropipette, fluorescein isothiocyanate–dextran (FITC-dex) and artificial endolymph into scala media of anaesthetized guinea pigs, with subsequent imaging of the inner ear using Light Sheet Fluorescence Microscopy (LSFM) as a means to obtain highly resolved 3D visualization of fluid movements. Our results demonstrate endolymph movement into the utricle, semicircular canals and endolymphatic duct and sac when more than 2.5 μl of fluid had been injected into scala media, with no apparent movement of fluid into the perilymphatic compartments. There was no movement of endolymph into these compartments when less than 2.5 μl was injected. The remarkable uptake of the FITC-dex into the endolymphatic duct, including an absorption into the periductal channels surrounding the endolymphatic duct, highlights the functional role this structure plays in endolymph volume regulation. [ABSTRACT FROM AUTHOR]

Auditory models have been developed for decades to simulate characteristics of the human auditory system, but it is often unknown how well auditory models compare to each other or perform in tasks they were not primarily designed for. This study systematically analyzes predictions of seven publicly-available cochlear filter models in response to a fixed set of stimuli to assess their capabilities of reproducing key aspects of human cochlear mechanics. The following features were assessed at frequencies of 0.5, 1, 2, 4, and 8 kHz: cochlear excitation patterns, nonlinear response growth, frequency selectivity, group delays, signal-in-noise processing, and amplitude modulation representation. For each task, the simulations were compared to available physiological data recorded in guinea pigs and gerbils as well as to human psychoacoustics data. The presented results provide application-oriented users with comprehensive information on the advantages, limitations and computation costs of these seven mainstream cochlear filter models. [ABSTRACT FROM AUTHOR]

Background: The photo-thermal effect has been hypothesised to be one of the most possible biophysical mechanisms for laser-cochlea stimulation. However, there is a lack of studies to date for direct assessing laser heating in humans due to the large body of evidence required to demonstrate safety and efficacy. Instead, the majority focus on animals like the guinea pig, from which a number of valuable results have been gained. However, in light of the increasing need to improve laser safety, it has became necessary to find out whether studies on animals can shed light on safe laser parameters in the human cochlea. Hence, we conducted this contrastive analysis of laser heating between the human and guinea pig cochlea with the aim of assisting further investigations in this field.Methods: In this work, a 3D symmetrical model was adopted to simplify the spiraled cochlea. With attention focused on the effect of heat conduction, the time-dependent heat equation was solved using finite element method with the COMSOL Script. In the simulations, cochleae with different sizes and various boundary thermal conditions were utilized.Results: Laser heating in both cochleae has a similar trend. In the first stage, or at the beginning of the laser heating, both cochleae increased their temperatures rapidly. In the second stage in which the laser heating reached a quasi-steady stage, the peak temperatures began to rise slowly as more laser pulses were applied. However, three differences of the laser heating were observed. The first is regarding the temperature rise. The results show that laser heating in guinea pig is higher than that in human under the same laser parameters. The second difference is the fluctuation of temperature rise at the center of the modiolus. There is a larger fluctuation of temperature rise in the guinea pig cochlea, compared with that in the human cochlea. The third one is the time for reaching a steady thermal state. The results show that the guinea pig cochlea takes longer time to reach a steady thermal state than the human cochlea. Those differences are mainly attributed to the distinctive thermal boundaries and the various sizes of the two cochleae.Conclusions: This study finds that the laser heating in the guinea pig cochlea is higher than that in the human cochlea under the condition of the same laser parameters. However, laser stimulation still displays a high spatial selectivity in both cochleae despite the effects of heat conduction. The results indicate that experimental studies on the guinea pig could appropriately be an alternative model for the sake of laser safety. [ABSTRACT FROM AUTHOR]

Goal: To validate a new electroanatomical model of the implanted guinea pig cochlea against independently obtained in vivo voltage tomography data, and evaluate the validity of exist-ing modeling assumptions on current paths and neural excitation. Methods: An in silico model was generated from sTSLIM images and analyzed in COMSOL Multiphysics. Tissue resistivities and boundary conditions were varied to test model sensitivity. Results: The simulation was most sensitive to the resistivities of bone, perilymph, and nerve. Bone tissue in particular should be separated by morphology because different types of bone have different electrical properties. Despite having a strong impact on intrascalar voltages and exit pathways, most boundary conditions, including a new alternative proposed to account for the unmodeled return path, only had a weak effect on neural excitation. Conclusion: The new model demonstrated a strong correlation with the in vivo voltage data. Significance: These findings address a long-standing knowledge gap about appropriate boundary conditions, and will help to promote wider acceptance of insights from computational models of the cochlea. [ABSTRACT FROM PUBLISHER]

Infrared neural stimulation ( INS) may be beneficial in auditory prostheses because of its spatially selective activation of spiral ganglion neurons. However, the response properties of single auditory neurons to INS and the possible contributions of its optoacoustic effects are yet to be examined. In this study, the temporal properties of auditory neurons in the central nucleus of the inferior colliculus ( ICC) of guinea pigs in response to INS were characterized. Spatial selectivity of INS was observed along the tonotopically organized ICC. Trains of laser pulses and trains of acoustic clicks were used to evoke single unit responses in ICC of normal hearing animals. In response to INS, ICC neurons showed lower limiting rates, longer latencies, and lower firing efficiencies. In deaf animals, ICC neurons could still be stimulated by INS while unresponsive to acoustic stimulation. The site and spatial selectivity of INS both likely shaped the temporal properties of ICC neurons. [ABSTRACT FROM AUTHOR]

Neurons of the lateral olivocochlear (LOC) system project from the auditory brainstem to the cochlea, where they synapse on radial dendrites of auditory nerve fibers. Selective LOC disruption depresses sound-evoked auditory nerve activity in the guinea pig, but enhances it in the mouse. Here, LOC disruption depressed spontaneous auditory nerve activity in the guinea pig. Recordings from single auditory nerve fibers revealed a significantly reduced proportion of fibers with the highest spontaneous firing rates (SRs) and an increased proportion of neurons with lower SRs. Ensemble activity, estimated using round window noise, also decreased after LOC disruption. Decreased spontaneous activity after LOC disruption may be a consequence of reduced tonic release of excitatory transmitters from the LOC terminals in guinea pigs. [ABSTRACT FROM AUTHOR]

Smoking has been positively associated with hearing loss in human. However, its effect on the cochlea has not been previously evaluated. Aim of work is to investigate the effect of nicotine, which is the primary pharmacological component of tobacco, on the structure of the cochlea of adult male guinea pigs. Fifteen male guinea pigs were classified into two groups: group I (control) and group II (nicotine treated group). Group II was further subdivided into two subgroups; IIA and IIB according to the dose of nicotine (3 mg/kg and 6 mg/kg, respectively). The cochlea was harvested and processed for light microscopy, transmission electron microscopy and scanning electron microscopy. Nicotine administration induced damage of outer hair cells which were distorted in shape with vacuolated cytoplasm and heterochromatic nuclei. Topography revealed damage of the stereocilia which included disorganization, bent and limp or complete loss and expansion of the surrounding supporting cells. These changes were more pronounced in the basal turn of the cochlea and mainly involved the outer hair cells. High dose induced more damage and resulted in protrusion of the apical poles of hair cells (blebing), particularly the outer two rows. Nicotine is proved to be harmful to the cells of the cochlea, particularly the outer hair cells of the basal turn. High doses induce blebing of hair cells. [ABSTRACT FROM AUTHOR]

Increased neuronal spontaneous firing rates have been observed throughout the central auditory system after trauma to the cochlea and this hyperactivity is believed to be associated with the phantom perception of tinnitus. Previously,we have shownin an animal model of hearing loss, that an acute injection with furosemide can significantly decrease hyperactivity after cochlear trauma and eliminate behavioral evidence of tinnitus of early onset. However, furosemide also has the potential to affect cochlear thresholds. In this paper, we measured the effects of a chronic (daily injections for 7 days) furosemide treatment on the spontaneous firing rate of inferior colliculus neurons and on cochlear thresholds in order to establish whether a beneficial effect on hyperactivity can be obtained without causing additional hearing loss. Guinea pigswere exposed to a 10-kHz, 124 dB, 2 h acoustic trauma, and after 5 days of recovery, were given daily i.p. injections of 80 mg/kg furosemide or an equivalent amount of saline. The activity of single IC neurons was recorded 24 h following the last injection. The furosemide treatment had no effect on cochlear thresholds compared to saline injections but did result in significant reductions in spontaneous firing rates recorded in inferior colliculus. These results that suggest a long-term beneficial effect of furosemide on hyperactivity after cochlear trauma may be achievable without detrimental effects on hearing, which is important when considering therapeutic potential. [ABSTRACT FROM AUTHOR]

The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed to promote the regeneration of sensory hair cells in the mature cochlea and their reconnection with auditory neurons through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and the introduction of neurotrophic factors. Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening. Guinea pigs treated with ATOH1 gene therapy, alone, had a significantly greater number of cells expressing hair cell markers compared to the contralateral non-treated cochlea when examined 3 weeks post-treatment. This increase, however, did not result in a commensurate improvement in hearing thresholds, nor was there an increase in synaptic ribbons, as measured by CtBP2 puncta after ATOH1 treatment alone, or when combined with neurotrophins. However, hair cell formation and synaptogenesis after co-treatment with ATOH1 and neurotrophic factors remain inconclusive as viral transduction was reduced due to the halving of viral titres when the samples were combined. Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness. [ABSTRACT FROM AUTHOR]

Background Notch signaling plays a crucial role in the fate determination of cochlear progenitor cells, hair cells, and supporting cells in the developing cochlea. Recent studies have demonstrated the temporal activation of Notch signaling in damaged mature cochleae, and have demonstrated the induction of new hair cells by pharmacologically inhibiting Notch signaling. The present study aimed to illustrate the feasibility of pharmacologically inhibiting Notch signaling by using a gamma-secretase inhibitor for treating sensorineural hearing loss. Results The effect of the sustained local delivery of MDL28170, a gamma-secretase inhibitor, on hearing and hair cell induction was tested in a guinea pig model with noise-induced hearing loss. MDL28170 was directly delivered into the cochlear fluids via a micro osmotic-pump. Drug application was initiated 7 days after noise exposure. Measurements of auditory brainstem responses revealed better hearing in the MDL28170-treated animals than in the vehicle controls. Histological analysis demonstrated a higher number of outer hair cells in the MDL28170-treated cochleae than the vehicle-treated cochleae. Conclusion These findings strongly suggest that local sustained delivery of a gamma-secretase inhibitor into the cochlea could be a novel strategy for treating acute hearing loss that is refractory to conventional treatment. [ABSTRACT FROM AUTHOR]

Pulsed near-infrared radiation has been proposed as an alternative stimulus for auditory nerve stimulation and could be potentially used in the design of cochlear implant. Although the infrared with high absorption coefficient of water (i.e., wavelength ranged from 1.8 to 2.2 μm) has been widely investigated, the lymph in the cochlea absorbs most of the infrared energies, and only a small part can arrive at the target auditory nerves. The present study is aimed to test whether the short-wavelength near-infrared irradiation with lower absorption coefficients can penetrate the lymph fluid to stimulate the auditory nerves. An 808-nm near-infrared laser was chosen to stimulate the auditory nerve in the guinea pig cochlea. The infrared pulse was delivered by an optical fiber that was surgically inserted near the round window membrane and oriented toward the spiral ganglion cells in the basal turn of the cochlea. The 2-Hz infrared pulses were used to stimulate the cochlea before and after the deafness with different pulse durations (100-1,000 μs). Optically evoked compound action potentials (oCAPs) were recorded during the infrared radiation. We successfully recorded oCAPs from both normal hearing animals and deafened animals. The oCAP amplitude increased with the infrared radiation energy. The preliminary experiment suggests that the near-infrared with lower absorption coefficients can effectively pass through the lymph filled in the cochlea and stimulate the auditory nerve. Further studies will optimize the deafness animal model and determine the optimal stimulation parameters. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The present study aimed to examine whether an E-prostanoid receptor 4 (EP4) agonist has superior protective effects to those of prostaglandin E1 (PGE1) in a guinea pig model of noise trauma. Methods: Drugs were locally applied on the round window membrane of guinea pig cochleae, followed by exposure of the test animals to intense noise. Protective effects mediated by an EP4 agonist were compared with those mediated by PGE1. Auditory function was monitored by measurements of the auditory brainstem response (ABR), and histological damage was assessed by immunohistochemical analysis of cochlear specimens. Results: Animals treated with an EP4 agonist exhibited significantly better hearing recovery than those pretreated with PGE1. Histologically, the numbers of remaining outer hair cells in cochleae treated with the EP4 agonist were significantly higher than in those treated with PGE1. Conclusion: The selective activation of EP4 has a stronger protective effect on cochleae against noise trauma than does the broad activation of EPs by PGE1. [Copyright &y& Elsevier]

Previous studies have shown that the vestibular short-latency-evoked potential (VsEP) in response to the brief head acceleration stimulus is a compound action potential of neurons innervating the otolith organs. However, due to the lack of direct evidence, it is currently unclear whether the VsEP is primarily generated by the activity of utricular or saccular afferent neurons, or some mixture of the two. Here, we investigated the origin of the VsEP evoked by brief bone-conducted vibration pulses in guinea pigs, using selective destruction of the cochlea, semicircular canals (SCCs), saccule, or utricle, along with neural blockade with tetrodotoxin (TTX) application, and mechanical displacements of the surgically exposed utricular macula. To access each end organ, either a dorsal or a ventral surgical approach was used. TTX application abolished the VsEP, supporting the neurogenic origin of the response. Selective cochlear, SCCs, or saccular destruction had no significant effect on VsEP amplitude, whereas utricular destruction abolished the VsEP completely. Displacement of the utricular membrane changed the VsEP amplitude in a non-monotonic fashion. These results suggest that the VsEP evoked by BCV in guinea pigs represents almost entirely a utricular response. Furthermore, it suggests that displacements of the utricular macula may alter its response to bone-conduction stimuli. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoids (GCs) are widely used to treat sudden sensorineural hearing loss (SSNHL) and significantly improve hearing. However, GC insensitivity has been observed in some patients of SSNHL. Objective: To study the correlation between GR expression in peripheral blood mononuclear cells (PBMCs) and in the cochlea of guinea pigs at mRNA and protein levels. Methods: One group of guinea pigs received dexamethasone (10 mg/kg/day) intraperitoneally for 7 consecutive days (dexamethasone group), and another group of guinea pigs received normal saline (control group). Real time PCR and Western blotting were used to detect the expression of GR mRNA and GR protein in PBMCs and the cochleae. Results: The GR mRNA and GR protein were detected in both PBMCs and the cochlear tissue of guinea pigs. GR mRNA and GR protein levels in PBMCs were positively correlated with those in the cochlea. The expression of GR mRNA and GR protein was significantly increased in the dexamethasone group compared to the control group. Conclusions: Levels of GR mRNA and GR protein in the PBMCs were positively correlated with those in the cochlea of guinea pigs. Systemic dexamethasone treatment can significantly up-regulate GR expression in PBMCs and in the cochlea. Measurement of the GR level in PBMCs could be used as an indicator of GR level in the cochlea. [ABSTRACT FROM AUTHOR]

Decreasing body size has been suggested as the third universal biological response to global warming after latitudinal/altitudinal range shifts and shifts in phenology. Size shifts in a community can be the composite result of intraspecific size shifts and of shifts between differently sized species. Metabolic explanations for the size shifts dominate in the literature but top down effects, i.e. intensified size-selective consumption at higher temperatures, have been proposed as alternative explanation. Therefore, we performed phytoplankton experiments with a factorial combination of warming and consumer type (protist feeding mainly on small algae vs. copepods mainly feeding on large algae). Natural phytoplankton was exposed to 3 (1st experiment) or 4 (2nd experiment) temperature levels and 3 (1st experiment: nano-, microzooplankton, copepods) or 2 (2nd experiment: microzooplankton, copepods) types of consumers. Size shifts of individual phytoplankton species and community mean size were analyzed. Both, mean cell size of most of the individual species and mean community cell size decreased with temperature under all grazing regimes. Grazing by copepods caused an additional reduction in cell size. Our results reject the hypothesis, that intensified size selective consumption at higher temperature would be the dominant explanation of decreasing body size. In this case, the size reduction would have taken place only in the copepod treatments but not in the treatments with protist grazing (nano- and microzooplankton). [ABSTRACT FROM AUTHOR]

Abstract: The present study aimed to clarify the protective effect of adenosine receptors against the excitotoxicity of cochlear afferent dendrites. The effects of 2-chloro-N6-cyclopentyladenosine (CCPA), an A1 adenosine receptor agonist, and 5′-N-cyclopropyl-carboxamidoadenosine (CPCA), an A2A adenosine receptor agonist, on cochlear excitotoxicity induced by kainic acid (KA) were examined using guinea pigs. KA was applied to the round window membrane at a concentration of 10mM for 30min. CCPA or CPCA was given at the onset of KA application. KA morphologically induced the swelling of cochlear afferent dendrites and significantly elevated the threshold of the compound action potential (CAP) of the cochlea. CCPA inhibited the KA-induced CAP threshold shift and swelling of the cochlear afferent dendrites. However, CPCA did not affect cochlear excitotoxicity induced by KA. The results suggest that adenosine A1 receptor activation could prevent the excitotoxicity of cochlear afferent dendrites. [Copyright &y& Elsevier]

The auditory portion of the inner ear, the cochlea, is an ideal organ for local gene transfection owing to its relative isolation. Various carriers have been tested for cochlear gene transfection. To date, viral vectors appear to have much higher transfection efficacy than non-viral mechanisms. Among these vectors, recombinant adeno-associated virus (rAAV) vectors have several advantages such as being non-pathogenic and the ability to produce prolonged gene expression in various cell types. However, rAAV vectors cannot pass through the intact round window membrane (RWM), otherwise a very attractive approach to access the human inner ear. In this study, performed in guinea-pigs, we describe a method to increase the permeability of RWM to rAAV vectors by partial digestion with collagenase solution. Elevated delivery of rAAV across the partially digested RWM increased transfection efficacy to a satisfactory level, even though it was still lower than that achieved by direct cochleostomy injection. Functional tests (auditory brainstem responses) showed that this enzymatic manipulation did not cause permanent hearing loss if applied appropriately. Morphological observations suggested that the damage to RWM caused by partial digestion healed within four weeks. Taken together, these findings suggest that partial digestion of the RWM is a safe and effective method for increasing the transfection of cochlear sensory cells with rAAV. [ABSTRACT FROM AUTHOR]

Abstract: Classic theories of hearing have considered only a translational component (piston-like component) of the stapes motion as being the effective stimulus for cochlear activation and thus the sensation of hearing. Our previous study () qualitatively showed that rotational components around the long and short axes of the footplate (rocking-like components) lead to cochlear activation as well. In this study, the contribution of the piston-like and rocking-like components of the stapes motion to cochlea activation was quantitatively investigated with measurements in live guinea pigs and a related mathematical description. The isolated stapes in anesthetized guinea pigs was stimulated by a three-axis piezoelectric actuator, and 3-D motions of the stapes and compound action potential (CAP) of the cochlea were measured simultaneously. The measured values were used to fit a hypothesis of the CAP as a linear combination of the logarithms of the piston-like and rocking-like components. Both the piston-like and rocking-like components activate cochlear responses when they exceed certain thresholds. These thresholds as well as the relation between CAP and intensity of the motion component were different for piston-like and rocking-like components. The threshold was found to be higher and the sensitivity lower for the rocking-like component than the corresponding values for the piston-like component. The influence of the rocking-like component was secondary in cases of piston-dominant motions of the stapes although it may become significant for low amplitudes of the piston-like component. [Copyright &y& Elsevier]

Abstract: It has been demonstrated that INS can be utilized to stimulate spiral ganglion cells in the cochlea. Although neural stimulation can be achieved without direct contact of the radiation source and the tissue, the presence of fluids or bone between the target structure and the radiation source may lead to absorption or scattering of the radiation, which may limit the efficacy of INS. The present study demonstrates the neural structures in the radiation beam path that can be stimulated. Histological reconstructions and microCT of guinea pig cochleae stimulated with an infrared laser suggest that the orientation of the beam from the optical fiber determined the site of stimulation in the cochlea. Best frequencies of the INS-evoked neural responses obtained from the central nucleus of the inferior colliculus matched the histological sites in the spiral ganglion. [Copyright &y& Elsevier]

Purpose: Thiosulfate may reduce cisplatin-induced ototoxicity, most likely by relieving oxidative stress and by forming inactive platinum complexes. This study aimed to determine the concentration and protective effect of thiosulfate in the cochlea after application of a thiosulfate-containing high viscosity formulation of sodium hyaluronan (HYA gel) to the middle ear prior to i.v. injection of cisplatin in a guinea pig model. Methods: The release of thiosulfate (0.1 M) from HYA gel (0.5% w/w) was explored in vitro. Thiosulfate in the scala tympani perilymph of the cochlea 1 and 3 h after application of thiosulfate in HYA gel to the middle ear was quantified with HPLC and fluorescence detection. Thiosulfate in blood and CSF was also explored. The potential otoprotective effect was evaluated by hair cell count after treatment with thiosulfate in HYA gel applied to the middle ear 3 h prior to cisplatin injection (8 mg/kg b.w.). Results: HYA did not impede the release of thiosulfate. Middle ear administration of thiosulfate in HYA gel gave high concentrations in the scala tympani perilymph while maintaining low levels in blood, and it protected against cisplatin-induced hair cell loss. Conclusion: HYA gel is an effective vehicle for administration of thiosulfate to the middle ear. Local application of a thiosulfate-containing HYA gel reduces the ototoxicity of cisplatin most likely without compromising its antineoplastic effect. This provides a minimally invasive protective treatment that can easily be repeated if necessary. [ABSTRACT FROM AUTHOR]

Abstract: Although salicylate is one of the most widely used nonsteroidal anti-inflammatory drugs, it causes moderate hearing loss and tinnitus at high-dose levels. In the present study, salicylate effects on the K currents in inner hair cells were examined. Salicylate reversibly reduced the outward K currents (I K,f), but did not affect the inward current (I K,n). Salicylate blocked the outward K currents in a concentration-dependent manner according to Hill equation with a half-blocking concentration of 1.66mM, and the Hill coefficient of 1.86. [Copyright &y& Elsevier]

Surgical human cochlear specimens were obtained during the removal of large posterior cranial fossa meningioma by a transcochlear approach in which the cochlea was removed for maximal exposure of the tumor and protection of important structures, such as the brainstem, cranial nerves, and pivotal blood vessels. The cochlear tissue was fixed and cryo-sectioned for tyrosine kinase receptor B (TrkB) and brain-derived neurotrophic factor (BDNF) immunohistochemistry. TrkB receptor protein was expressed in both neuronal somata and the processes of human spiral ganglion neurons (SGNs). In the human organ of Corti, TrkB immunoreactivity was mainly present in nerve fibers underneath outer hair cells. BDNF expression was found neither in the organ of Corti nor in the spiral ganglion of human cochlea. For antibody specificity and for control and comparative purposes, TrkB immunocytochemistry was performed in primary cultures of cochlear neuron/glia from adult guinea pig. Confocal laser scanning microscopy showed that TrkB was homogeneously distributed in the cytoplasm of both neuronal somata and axons. Knowledge of the expression of TrkB receptor in human cochlea should help to determine the target structures for neuron preservation in hearing-impaired patients. Our results indicate that the regeneration of SGNs under pathological conditions can be enhanced with BDNF/TrkB-based pharmaceutical or genetic strategies. [ABSTRACT FROM AUTHOR]

Abstract: Reciprocating drug delivery is a means of delivering soluble drugs directly to closed fluid spaces in the body via a single cannula without an accompanying fluid volume change. It is ideally suited for drug delivery into small, sensitive and unique fluid spaces such as the cochlea. We characterized the pharmacokinetics of reciprocating drug delivery to the scala tympani within the cochlea by measuring the effects of changes in flow parameters on the distribution of drug throughout the length of the cochlea. Distribution was assessed by monitoring the effects of DNQX, a reversible glutamate receptor blocker, delivered directly to the inner ear of guinea pigs using reciprocating flow profiles. We then modeled the effects of those parameters on distribution using both an iterative curve-fitting approach and a computational fluid dynamic model. Our findings are consistent with the hypothesis that reciprocating delivery distributes the drug into a volume in the base of the cochlea, and suggest that the primary determinant of distribution throughout more distal regions of the cochlea is diffusion. Increases in flow rate distributed the drug into a larger volume that extended more apically. Over short time courses (less than 2h), the apical extension, though small, significantly enhanced apically directed delivery of drug. Over longer time courses (>5h) or greater distances (>3mm), maintenance of drug concentration in the basal scala tympani may prove more advantageous for extending apical delivery than increases in flow rate. These observations demonstrate that this reciprocating technology is capable of providing controlled delivery kinetics to the closed fluid space in the cochlea, and may be suitable for other applications such as localized brain and retinal delivery. [Copyright &y& Elsevier]

Salicylate-induced ototoxicity leading to sensorineural hearing loss (SNHL) and tinnitus is well documented. However, the exact mechanisms are poorly defined. Caspase-3 is a member of the class of effector caspases and has been activated in nearly every model of apoptosis. To examine its role in salicylate-induced injury, we subjected guinea pigs to treatment with a specific inhibitor zDEVD-FMK via the round window niche (RWN) followed by a systemic injection of salicylate at a dose of 200 mg·kg·d i.p. for 10 consecutive days. For those animals administered with salicylate, immunohistochemical studies revealed that caspase-3 was activated in the spiral ganglion neurons (SGNs) and method of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) to identify neuronal apoptosis showed that fragmented nuclei were distributed in Rosenthal's canal. Topical administration of the zDEVD-FMK at a concentration of 500 mM blocked caspase-3 activation and had an effect in reducing the number of TUNEL-positive auditory neurons. In contrast, the inhibitor at a concentration of 125 or 250 mM caused no variation in the expression of activated caspase-3, or in the ratio of TUNEL-positive neurons. These results indicate that caspase-3 is a crucial mediator of apoptosis induced by salicylate in the primary auditory neuron in vivo, and suggest that the specific inhibitor at a relatively high concentration may be therapeutically beneficial in salicylate-induced apoptosis. [ABSTRACT FROM AUTHOR]

Intratympanic (IT) delivery of drugs to the ear is increasingly used for both clinical and research purposes. One limitation of IT delivery is that drugs are rapidly lost from the middle ear by a number of processes, so that prolonged delivery of drug is technically difficult. In the present study, the delivery characteristics of a poloxamer hydrogel formulation containing dexamethasone (dex) were evaluated. The gel is liquid at room temperature, allowing IT injection, but transitions to a gel at body temperature, providing a prolonged residence time in the middle ear. A 50-μl volume of control or dex-containing gel (dex-gel) was injected through the tympanic membrane of guinea pigs. Cochlear function was assessed with cochlear action potential and acoustic emission thresholds measured immediately, 6 or 24 h after IT gel injection. After 6- or 24-hour treatment with dex-gel, perilymph drug gradients along the cochlea were assessed by taking samples sequentially from the apex, and endolymph was sampled from the basal turn. Control gel injections caused small changes in sound field calibrations and functional measures for low-frequency stimuli, consistent with an induced conductive loss. Within 24 h, responses returned to normal. Twenty-four hours after dex-gel injection, low-frequency changes remained as the dex-gel was retained better in the middle ear, but there was no indication of high-frequency loss. While perilymph sample data showed that dex gradients were substantially lower than after single injections of dex solution, quantitative analysis of this result suggests that some dex may have entered the perilymph through the thin bone in the apical region of the cochlea. Endolymph levels of dex remained lower than those in the perilymph. This study confirms that a poloxamer hydrogel-based dex formulation provides an effective method for a prolonged delivery, providing a more uniform distribution of drug in the inner ear. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Exogenous neurotrophin delivery to the deaf cochlea can prevent deafness-induced auditory neuron degeneration, however, we have previously reported that these survival effects are rapidly lost if the treatment stops. In addition, there are concerns that current experimental techniques are not safe enough to be used clinically. Therefore, for such treatments to be clinically transferable, methods of neurotrophin treatment that are safe, biocompatible and can support long-term auditory neuron survival are necessary. Cell transplantation and gene transfer, combined with encapsulation technologies, have the potential to address these issues. This study investigated the survival-promoting effects of encapsulated BDNF over-expressing Schwann cells on auditory neurons in the deaf guinea pig. In comparison to control (empty) capsules, there was significantly greater auditory neuron survival following the cell-based BDNF treatment. Concurrent use of a cochlear implant is expected to result in even greater auditory neuron survival, and provide a clinically relevant method to support auditory neuron survival that may lead to improved speech perception and language outcomes for cochlear implant patients. [ABSTRACT FROM AUTHOR]

Abstract: It has been shown that molecular hydrogen acts as a therapeutic and preventive antioxidant by selectively reducing the hydroxyl radical, the most cytotoxic of the reactive oxygen species. In the present study, we tested the hypothesis that acoustic damage in guinea pigs can be attenuated by the consumption of molecular hydrogen. Guinea pigs received normal water or hydrogen-rich water for 14 days before they were exposed to 115dB SPL 4-kHz octave band noise for 3h. Animals in each group underwent measurements for auditory brainstem response (ABR) or distortion-product otoacoustic emissions (DPOAEs) before the treatment (baseline) and immediately, 1, 3, 7, and 14 days after noise exposure. The ABR thresholds at 2 and 4kHz were significantly better on post-noise days 1, 3, and 14 in hydrogen-treated animals when compared to the normal water-treated controls. Compared to the controls, the hydrogen-treated animals showed greater amplitude of DPOAE input/output growth functions during the recovery process, with statistical significance detected on post-noise days 3 and 7. These findings suggest that hydrogen can facilitate the recovery of hair cell function and attenuate noise-induced temporary hearing loss. [ABSTRACT FROM AUTHOR]

2-Aminoethoxydiphenyl borate (2-APB) analogs are potentially better vascular gap junction blockers than others widely used, but they remain to be characterized. Using whole cell and intracellular recording techniques, we studied the actions of 2-APB and its potent analog diphenylborinic anhydride (DPBA) on vascular smooth muscle cells (VSMCs) and endothelial cells in situ of or dissociated from arteriolar segments of the cochlear spiral modiolar artery, brain artery, and mesenteric artery. We found that both 2-APB and DPBA reversibly suppressed the input conductance (Ginput) of in situ VSMCs (IC50 ≈ 4-8 μM). Complete electrical isolation of the recorded VSMC was achieved at 100 μM. A similar gap junction blockade was observed in endothelial cell tubules of the spiral modiolar artery. Similar to the action of 18β-glycyrrhetinic acid (18β-GA), 2-APB and DPBA depolarized VSMCs. In dissociated VSMCs, 2-APB and DPBA inhibited the delayed rectifier K+ current (IK) with an IC50 of ∼120 μM in the three vessels but with no significant effect on Ginput or the current-voltage relation between -140 and -40 mV. 2-APB inhibition of IK was more pronounced at potentials of ≤20 mV than at +40 mV and more marked on the fast component than on the slow component, which was mimicked by 4-aminopyridine but not by tetraethylammonium, nitrendipine, or charybdotoxin. In contrast, 18β-GA caused a linear inhibition of IK between 0 to +40 mV, which was similar to the action of tetraethylammonium or charybdotoxin. Finally, the 2-APB-induced inhibition of electrical coupling and IK was not affected by the inositol 1,4,5-trisphosphate receptor antagonist xestospongin C. We conclude that 2-APB analogs are a class of potent and reversible vascular gap junction blockers with a weak side effect of voltage-gated K+ channel inhibition. They could be gap junction blockers superior to 18β-GA only when Ca2+-actived K+ channel inhibition by the latter is a concern but inositol 1,4,5-trisphosphate receptor and voltage-gated K+ channel inhibitions are not. [ABSTRACT FROM AUTHOR]

Abstract: Hearing impairment is a worldwide health problem. Employing semi-quantitative immunological detection methods, we found that the apoptosis inhibitor protein Birc5 is expressed in cell types critical for hearing perception. In the guinea pig model, moderate noise exposure causing only a temporary mean hearing impairment of 33dB significantly enhanced Birc5 expression in the spiral ligament, nerve fibers and the organ of Corti. In contrast, intratympanic gentamicin injection inducing permanent cell damage and mean hearing loss of 24dB correlated with a significant Birc5 downregulation in the ligament, nerve fibers and the organ of Corti. The cytoprotective activity of the guinea pig and human Birc5 protein was confirmed by cloning of the gene and by subsequent ectopic expression and challenging studies against the ototoxin gentamicin in epithelial and auditory cell models. As the mammalian cochlea is unable to regenerate upon damage, these data suggest that modulation of Birc5 expression may represent a novel physiological mechanism to protect the inner ear against stress-induced cell damage. Hence, the targeted modulation of Birc5 levels may lead to novel otoprotective therapeutic strategies. [Copyright &y& Elsevier]

Abstract: In the current study, we explored whether chronic salicylate exposure could induce apoptosis in outer hair cells (OHCs) and spiral ganglion neurons (SGNs) of the cochlea. Guinea pig received sodium salicylate (400mg/kg/d) or saline vehicle for 10 consecutive days. Programmed cell death (PCD) executioner was evaluated with immunohistochemistry detection of activated caspase-3. Apoptosis was examined with a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method. Repeated salicylate administration activated caspase-3 and caused apoptosis in OHCs and SGNs (p <0.01 vs. saline control for both measures and in both cell types). Cell counting showed a significant loss in OHCs (p <0.01 vs. saline control), but not in inner hair cells (IHCs). Transmission electron microscopy (TEM) revealed chromatin condensation and nucleus margination in salicylate-treated cochlea. Scanning electron microscopy (SEM) demonstrated stereociliary bundles breakdown and fusion at the apical of OHCs, villous matter was discovered to attach on the surface of SGNs. These findings suggest that long-term administration of high-dose salicylate can activate caspase-3 pathway to induce OHC and SGN apoptosis. [Copyright &y& Elsevier]

Abstract: 3-Nitropropionic acid (3-NP) induces hearing loss by impairing mitochondrial energy generation. Geranylgeranylacetone (GGA) is known to protect the cochlea from various injuries. The present study was designed to investigate the protective effect of GGA against acute 3-NP-induced damage to the cochlear mitochondria. Female Hartley guinea pigs were divided into 4 groups. The 3-NP vehicle was injected to control animals and in animals receiving GGA alone, only GGA was administered for 7 days. 3-NP (500mM, 4μl) was administered with (animals receiving both GGA and 3-NP) or without (animals receiving 3-NP alone) GGA pretreatment (800mg/kg, 7 days). The auditory brainstem response (ABR) was recorded at click and at 8, 16 and 32kHz before and after injection, respectively. After cochlear harvest, hematoxylin/eosin staining and immunohistochemistry for anti-HSP70 antibody were done. 3-NP exposure resulted in elevated ABR thresholds that exceeded the maximum recording limit, while GGA pretreatment before 3-NP exposure led to a significant decrease in hearing threshold shift. Histological analysis of above former group revealed loss of type II fibrocytes in the spiral ligament, hair cells in the organ of Corti, stellate fibrocytes in the spiral limbus and spiral ganglion cells, while in above latter group, these cells were preserved. Control animals revealed weak HSP70 expression in the nuclei of some supporting cells (pillar cells, Deiters’ cells and Hensen''s cells) and interdental cells. Animals receiving GGA alone showed strong HSP70 expression in the same area as in control animals, while animals receiving both GGA and 3-NP demonstrated slightly decreased HSP70 expression in that area. These results suggest that GGA may protect the cochlea against acute injury resulting from mitochondrial dysfunction. [Copyright &y& Elsevier]

Abstract: Sensory organs typically use receptor cells and afferent neurons to transduce environmental signals and transmit them to the CNS. When sensory cells are lost, nerves often regress from the sensory area. Therapeutic and regenerative approaches would benefit from the presence of nerve fibers in the tissue. In the hearing system, retraction of afferent innervation may accompany the degeneration of auditory hair cells that is associated with permanent hearing loss. The only therapy currently available for cases with severe or complete loss of hair cells is the cochlear implant auditory prosthesis. To enhance the therapeutic benefits of a cochlear implant, it is necessary to attract nerve fibers back into the cochlear epithelium. Here we show that forced expression of the neurotrophin gene BDNF in epithelial or mesothelial cells that remain in the deaf ear induces robust regrowth of nerve fibers towards the cells that secrete the neurotrophin, and results in re-innervation of the sensory area. The process of neurotrophin-induced neuronal regeneration is accompanied by significant preservation of the spiral ganglion cells. The ability to regrow nerve fibers into the basilar membrane area and protect the auditory nerve will enhance performance of cochlear implants and augment future cell replacement therapies such as stem cell implantation or induced transdifferentiation. This model also provides a general experimental stage for drawing nerve fibers into a tissue devoid of neurons, and studying the interaction between the nerve fibers and the tissue. [Copyright &y& Elsevier]

Objective: We investigated the otoprotective effect of methylprednisolone against cisplatin-induced ototoxicity by comparing the effectiveness of route of administration. Materials and Methods: Thirty-five adult, albino guinea pigs were randomly divided into 5 groups and were treated as follows: Group (1) received cisplatin alone 13 mg/kg, (2) intratympanic methylprednisolone alone, (3) cisplatin and intratympanic methylprednisolone, (4) intravenous methylprednisolone alone, (5) cisplatin and intravenous methylprednisolone. Baseline and 72 hours post-treatment distortion product otoacustic emissions were measured. Cochleae were harvested and processed for electron microscopic examination after completion of auditory testing. Results: Mean post-treatment distortion product otoacustic emission amplitudes significantly decreased in group 1 at 6 to 8 kHz (p=0.000). There were no significant differences between pretreatment and posttreatment DPOAE amplitudes in group 3 animals suggesting that intratympanic methylprednisolone had an otoprotective effect (p>0.05). Although significant otoprotection was not observed in group 5 animals, the measurements were close to significance (p<0.05). There were no significant differences in emission amplitudes between before and after methylprednisolone injections in group 2 and 4 animals (p>0.05). The electron microscopy observations demonstrated an increased intracytoplasmic myeline figures in the outer hair cells in group 1 animals whereas normal morphology of the outer hair cells was preserved in group 3 animals. Conclusion: These results demonstrate that intratympanic methylprednisolone protects against cisplatin ototoxicity. [ABSTRACT FROM AUTHOR]

Abstract: There is increasing interest in the use of electro-acoustical stimulation in people with a cochlear implant that have residual low-frequency hearing in the implanted ear. This raises the issue of how electrical and acoustical stimulation interact in the cochlea. We have investigated the effect of electrical stimulation on the acoustically evoked compound action potential (CAP) in normal-hearing guinea pigs. CAPs were evoked by tone bursts, and electric stimuli were delivered at the base of the cochlea using extracochlear electrodes. CAPs could be suppressed by electrical stimulation under various conditions. The dependence of CAP suppression on several parameters was investigated, including frequency and level of the acoustic stimulus, current level of the electric stimulus and the interval between electric and acoustic stimulus (EAI). Most pronounced suppression was observed when CAPs were evoked with high-frequency tones of low level. Suppression increased with current level and at high currents low-frequency evoked CAPs could also be suppressed. Suppression was typically absent several milliseconds after the electric stimulus. Suppression mediated by direct neural responses and hair cell mediated (electrophonic) responses is discussed. We conclude that the high-frequency part of the cochlea can be stimulated electrically with little detrimental effects on CAPs evoked by low-frequency tones. [Copyright &y& Elsevier]

Abstract: Noise over-stimulation may induce hair cells loss and hearing deficit. The c-myc oncogene is a major regulator for cell proliferation, growth, and apoptosis. However, the role of this gene in the mammalian cochlea is still unclear. The study was designed to firstly investigate its function under noise condition, from the aspect of cochlear ultrastructural changes. We had established the adenoviral vector of c-myc gene and delivered the adenovirus suspension into the scala tympani of guinea pigs 4days before noise exposure. The empty adenoviral vectors were injected as control. Then, all subjects were exposed to 4-kHz octave-band noise at 110dB SPL for 8h/day, 3days consecutively. Auditory thresholds were assessed by auditory brainstem response, prior to and 7days following noise exposure. On the seventh days after noise exposure, the cochlear sensory epithelia surface was observed microscopically and the cochleae were taken to study the ultrastructural changes. The results indicated that auditory threshold shift after noise exposure was higher in the ears treated with Ad.EGFP than that treated with Ad.c-myc-EGFP. Stereocilia loss and the disarrangement of outer hair cells were observed, with greater changes found in the Ad.EGFP group. Also, the ultrastructure changes were severe in the Ad.EGFP group, but not obvious in the Ad.c-myc-EGFP group. Therefore, c-myc gene might play an unexpected role in hearing functional and morphological protection from acoustic trauma. [Copyright &y& Elsevier]

Conclusion: These results suggest that noise induces free radical formation in the cochlea and that, in the guinea pig, heme oxygenase-1 (HO-1) may play an important role in the recovery from noise trauma in the organ of Corti. Objective: Free radicals are involved in noise-induced hearing loss. It has been demonstrated that the induction of HO-1 may protect cells exposed to oxidative challenge. The present study was designed to investigate the effect of intense noise exposure on HO-1 induction. Materials and methods: A total of 25 adult guinea pigs (body weight 200-300 g) with a normal Preyers's reflex were used as subjects. Based on preliminary tests, the appropriate intensities and durations of noise were determined that were adequate to induce apparent threshold shifts and lead to various recovery patterns to initial thresholds. The sound was routed through a power amplifier to a speaker, which was positioned directly over the animals in a sound chamber. Auditory brainstem response (ABR) testing, Western blot analysis for HO-1, and immunohistochemical testing were done. Results: Exposure of the guinea pigs to 115 dB SPL octave band noise for 5 h induced HO-1 expression in the organ of Corti. In the organ of Corti, HO-1 expression increased mainly in the outer hair cells. Some expression of HO-1 was observed before and after noise exposure in the supporting cells. HO-1 expression in the organ of Corti was definitely increased in guinea pigs with an intense noise exposure which causes a temporary threshold shift. [ABSTRACT FROM AUTHOR]

Abstract: In order to transduce sounds efficiently, the stereocilia of hair cells in the organ of Corti must be positioned optimally. Mechanical displacements, such as pressure differentials across the organ caused by endolymphatic hydrops, may impair sensitivity. Studying this phenomenon has been limited by the technical difficulty of inducing sustained displacements of stereocilia in vivo. We have found that small injections (0.5–2 μL) of Healon gel into the cochlear apex of guinea pigs produced sustained changes of endocochlear potential (EP), summating potential (SP) and transducer operating point (OP) in a manner consistent with a mechanically-induced position change of the organ of Corti in the basal turn. Induced changes immediately recovered when injection ceased. In addition, effects of low-frequency bias tones on EP, SP and OP were enhanced during the injection of gel and remained hypersensitive after injection ceased. This is thought to result from the viscous gel mechanically limiting pressure shunting through the helicotrema. Cochlear microphonics measured as frequency was varied showed enhancement below 100Hz but most notably in the sub-auditory range. Sensitivity to low-frequency biasing was also enhanced in animals with surgically-induced endolymphatic hydrops, suggesting that obstruction of the perilymphatic space by hydrops could contribute to the pathophysiology of this condition. [Copyright &y& Elsevier]

Abstract: During the development of the inner ear, the Notch cell signaling pathway is responsible for the specification of the pro-sensory domain and influences cell fate decisions. It is assumed that Notch signaling ends during maturity and cannot be reinitiated to alter the fate of new or existing cells in the organ of Corti. This is in contrast to non-mammalian species which reinitiate Delta1–Notch1 signaling in response to trauma in the auditory epithelium, resulting in hair cell regeneration through transdifferentiation and/or mitosis. We report immunohistochemical data and Western protein analysis showing that in the aminoglycoside-damaged guinea pig organ of Corti, there is an increase in proteins involved in Notch activation occurring within 24h of a chemical hair cell lesion. The signaling response is characterized by the increased presence of Jagged1 ligand in pillar and Deiters cells, Notch1 signal in surviving supporting cell nuclei, and the absence of Jagged2 and Delta-like1. The pro-sensory bHLH protein Atoh1 was absent at all time points following an ototoxic lesion, while the repressor bHLH transcription factors Hes1 and Hes5 were detected in surviving supporting cell nuclei in the former inner and outer hair cell areas, respectively. Notch pathway proteins peaked at 2 weeks, decreased at 1 month, and nearly disappeared by 2 months. These results indicate that the mammalian auditory epithelium retains the ability to regulate Notch signaling and Notch-dependent Hes activity in response to cellular trauma and that the signaling is transient. Additionally, since Hes activity antagonizes the transcription of pro-sensory Atoh1, the presence of Hes after a lesion may prohibit the occurrence of transdifferentiation in the surviving supporting cells. [Copyright &y& Elsevier]

Three-dimensional (3D) reconstruction of anatomical structures can give additional insight into the morphology and function of these structures. We compare 3D reconstructions of the guinea pig inner ear, using light microscopy and orthogonal plane fluorescence optical sectioning microscopy. Applications of 3D reconstruction of the inner ear are further explored. For each method two bullas were prepared for 3D reconstruction. Both methods are explained. In general, the 3D reconstructions using orthogonal plane fluorescence optical sectioning microscopy are superior to light microscopy. The exact spiral shape of the cochlea could be reconstructed using orthogonal plane fluorescence optical sectioning microscopy and the length of the basilar membrane measured. When a resolution of 20 μm is sufficient, orthogonal plane fluorescence optical sectioning microscopy is a superior technique for 3D reconstruction of inner ear structures in animals. [ABSTRACT FROM AUTHOR]

Abstract: Green fluorescent protein (GFP) has been used extensively to label cells in vitro and to track them following their transplantation in vivo. During our studies using the mouse embryonic stem cell line R1 B5-EGFP, we observed variable levels of fluorescence intensity of the GFP within these transfected cells. The variable fluorescence of this protein coupled with the innately autofluorescent nature of several structures within the cochlea collectively made the in vivo identification of these transplanted stem cells difficult. We have modified previously published protocols to enable the discrimination of an authentic GFP signal from autofluorescence in the adult guinea pig cochlea using fluorescence-based immunohistochemistry. The protocol described can also be used to label tissues of the cochlea using a chromogen, such as 3,3′-diaminobenzidine tetrahydrochloride (DAB). Moreover, the described method gives excellent preservation of structural morphology making the tissues useful for both morphological and quantitative studies in combination with robust immunohistochemistry in the adult guinea pig cochlea. [Copyright &y& Elsevier]

Conclusion. Mitochondrial dysfunction in the cochlea potentiates the ototoxicity of aminoglycosides. Objective. This study examined whether mitochondrial dysfunction in the cochlea affects the ototoxicity of aminoglycosides. Materials and methods. Nineteen guinea pigs were treated with the mitochondrial toxin 3-nitropropionic acid (3-NP), kanamycin, both agents, or normal saline as control. After 14 days, hair cell loss and auditory brainstem response (ABR) were assessed. Results. The administration of 400 mg/kg of kanamycin caused neither hair cell loss nor ABR threshold shift. Administration of 3-NP caused mild ABR threshold shift without significant hair cell loss. Administration of 3-NP and kanamycin caused ABR threshold shift and significant hair cell loss. [ABSTRACT FROM AUTHOR]

Conclusion. The results of this study indicate that coenzyme Q10 reduces cochlear oxidative stress induced by acoustic overstimulation. Objective. We investigated the effects of coenzyme Q10 on noise-induced hearing loss in guinea pigs. Materials and methods. Animals received water-soluble coenzyme Q10 intraperitoneally 2 h before noise exposure. Seven days after noise exposure (130 dB sound pressure level for 3 h), the auditory brainstem response (ABR) threshold shift and cochlear hair cell damage were assessed. Results. We observed that the ABR threshold shift was significantly less in the coenzyme Q10 group than in the vehicle control group. In addition, the percentage of missing outer hair cells was lower in the coenzyme Q10 group than in the control group. Moreover, 2 days after administration of coenzyme Q10, increased antioxidative activity in the cochlea, as measured by analysis of hydroxy radical scavenging activity by electron spin resonance was observed. [ABSTRACT FROM AUTHOR]

During and after an increase of inner ear pressure, induced by injection of artificial perilymph, the 2 f 1 − f 2 and f 2 − f 1 distortion products (DPs) in cochlear microphonics (CM) and otoacoustic emissions (OAE) were recorded in the guinea pig. An inner pressure increase of ∼600 Pa gave only small changes in CMDP and DPOAE. Along with a decrease in f 1 amplitude, a small decrease in amplitude of the 2 f 1 − f 2 and a small increase in the f 2 − f 1 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 2 f 1 − f 2 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 2 f 1 − f 2 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. [ABSTRACT FROM AUTHOR]

Several partial models of cochlear subparts are available. However, a complete 3D model of an intact cochlea based on actual histological sections has not been reported. Hence, the aim of this study was to develop a novel 3D model of the guinea pig cochlea and conduct post-processes on this reconstructed model. We used a combination of histochemical processing and the method of acquiring section data from the visible human project (VHP) to obtain a set of ideal raw images of cochlear sections. After semi-automatic registration and accurate manual segmentation with professional image processing software, one set of aligned data and six sets of segmented data were generated. Finally, the segmented structures were reconstructed by 3D Slicer (a professional imaging process and analysis tool). Further, post-processes including 3D visualization and a virtual endoscope were completed to improve visualization and simulate the course of the cochlear implant through the scala tympani. The 3D cochlea model contains the main six structures: (1) the inner wall, (2) modiolus and spiral lamina, (3) cochlea nerve and spiral ganglion, (4) spiral ligament and inferior wall of cochlear duct, (5) Reissner’s membrane and (6) tectorial membrane. Based on the results, we concluded that ideal raw images of cochlear sections can be acquired by combining the processes of conventional histochemistry and photographing while slicing. After several vital image processing and analysis steps, this could further generate a vivid 3D model of the intact cochlea complete with internal details. This novel 3D model has great potential in teaching, basic medical research and in several clinical applications. [ABSTRACT FROM AUTHOR]

Background and Purpose: Glycyrrhetinic acids (GAs) are widely used as gap junction blockers, but their efficacy and side effects have not been well determined.Experimental Approach: Whole-cell electrical recordings were made from vascular smooth muscle cells (VSMCs) embedded in or dissociated from, guinea pig cochlear artery segments.Key Results: 18beta- & 18alpha-GA concentration-dependently increased membrane input resistance (R(in)) of in situ VSMCs, with a maximal input conductance (G(in)=1/R(in)) reduction of 92% & 77% and IC(50) of 2.0 & 4.4 microm, respectively. 18betaGA (30 microM) resulted in a R(in) of 2.2 GOmega and C(in) of 12 pF, comparable to those of freshly dissociated VSMCs (3.1 GOmega & 6.1 pF). The GAs (> or =30 microM) caused a depolarization in VSMCs in situ. In dispersed VSMCs, they both inhibited delayed rectifiers; 18betaGA also activated a non-selective cation conductance while 18alphaGA inactivated a voltage-independent K+-conductance. ACh induced an outward current in VSMCs in situ at -40 mV, with a positive slope I/V relation and a reversal potential near E(K). The ACh-induced current was attenuated by 18beta- & 18alphaGA with an IC(50) of 4.3 & 7.8 microM, respectively.Conclusions and Implications: 18betaGA blocked the vascular gap junctions, achieving a complete electrical isolation of the recorded VSMC at > or =30 microM while causing a mild depolarization by a complex conductance alteration. 18betaGA suppressed the ACh-induced current in VSMC by blocking the myoendothelial gap junction and by a non-junctional action. 18alphaGA at 30-100 microM failed to fully block the gap junctions while exerting side actions. [ABSTRACT FROM AUTHOR]