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Delivery of pharmaceuticals to the cochleae of patients with auditory dysfunction could potentially have many benefits from enhancing auditory nerve survival to protecting remaining sensory cells and their neuronal connections. Treatment would require platforms to enable drug delivery directly to the cochlea and increase the potential efficacy of intervention. Cochlear implant recipients are a specific patient subset that could benefit from local drug delivery as more candidates have residual hearing; and since residual hearing directly contributes to post-implantation hearing outcomes, it requires protection from implant insertion-induced trauma. This study assessed the feasibility of utilizing microparticles for drug delivery into cochlear fluids, testing persistence, distribution, biocompatibility, and drug release characteristics. To allow for delivery of multiple therapeutics, particles were composed of two distinct compartments; one containing polylactide-co-glycolide (PLGA), and one composed of acetal-modified dextran and PLGA. Following in vivo infusion, image analysis revealed microparticle persistence in the cochlea for at least 7 days post-infusion, primarily in the first and second turns. The majority of subjects maintained or had only slight elevation in auditory brainstem response thresholds at 7 days post-infusion compared to pre-infusion baselines. There was only minor to limited loss of cochlear hair cells and negligible immune response based on CD45+ immunolabling. When Piribedil-loaded microparticles were infused, Piribedil was detectable within the cochlear fluids at 7 days post-infusion. These results indicate that segmented microparticles are relatively inert, can persist, release their contents, and be functionally and biologically compatible with cochlear function and therefore are promising vehicles for cochlear drug delivery. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1510-1522, 2016. [ABSTRACT FROM AUTHOR]

The inferior colliculus (IC) is a major center of integration in the ascending as well as descending auditory pathways, where both excitatory and inhibitory amino acid neurotransmitters play a key role. When normal input to the auditory system is decreased, the balance between excitation and inhibition in the IC is disturbed. We examined global changes in gene expression in the rat IC 3 and 21 days following bilateral deafening, using Affymetrix GeneChip arrays and focused our analysis on changes in expression of neurotransmission-related genes. Over 1400 probe sets in the Affymetrix Rat Genome U34A Array were identified as genes that were differentially expressed. These genes encoded proteins previously reported to change as a consequence of deafness, such as calbindin, as well as proteins not previously reported to be modulated by deafness, such as clathrin. A subset of 19 differentially expressed genes was further examined using quantitative RT–PCR at 3, 21 and 90 days following deafness. These included several GABA, glycine, glutamate receptor and neuropeptide-related genes. Expression of genes for GABA-A receptor subunitsβ2,β3, andγ2, plus ionotropic glutamate receptor subunits AMPA 2, AMPA 3, and kainate 2, increased at all three times. Expression of glycine receptor α1 initially declined and then later increased, whileα2 increased sharply at 21 days. Glycine receptorα3 increased between 3 and 21 days, but decreased at 90 days. Of the neuropeptide-related genes tested with qRT–PCR, tyrosine hydroxylase decreased approximately 50% at all times tested. Serotonin receptor 2C increased at 3, 21, and 90 days. The 5B serotonin receptor decreased at 3 and 21 days and returned to normal by 90 days. Of the genes tested with qRT–PCR, only glycine receptorα2 and serotonin receptor 5B returned to normal levels of expression at 90 days. Changes in GABA receptorβ3, GABA receptor γ2, glutamate receptor 2/3, enkephalin, and tyrosine hydroxylase were further confirmed using immunocytochemistry. [ABSTRACT FROM AUTHOR]

The transient expression of stress proteins in cells exposed to adverse environmental conditions is thought to provide a survival advantage. In the present study, the expression of the major mammalian stress protein, Hsp72, was characterized in the rat peripheral auditory system following varying periods of unilateral cochlear ischemia and reperfusion. Western blot analysis of whole cochlear homogenates revealed Hsp72 expression after as little as 5 minutes of cochlear ischemia. Cochlear Hsp72 immunoreactivity following 10 minutes of ischemia was observed within 2 hours, remained evident through 6 hours, and decreased toward control levels by 12 hours. Preliminary immunocytochemical localization data revealed Hsp72 expression in the outer hair cells. The characterization of Hsp72 expression following transient ischemia represents the first step toward understanding the role that stress proteins have in the protection of the mammalian auditory system. [ABSTRACT FROM AUTHOR]

The presence of immune-mediated hearing loss was investigated in an animal model. Eight guinea pigs and four mice underwent immunizations with a preparation of chick or guinea pig cochlear tissue and Freund's adjuvant. Hearing thresholds were monitored by auditory brainstem response (ABR) testing over a 5-week period after immunization. The serum and temporal bones of test and control animals were then examined using an enzyme-linked im-munosorbent assay (ELISA), immunocytochemical, and his-tological techniques. Hearing loss of 20 dB or greater occurred in eight animals. ELISA demonstrated antibodies to cochlear antigens in the sera of all test animals. Immunocytochemistry revealed immunostaining of hair cell stereocilia in the organ of Corti and saccule. Endolymphatic hydrops, and organ of Corti degeneration was observed in the temporal bones of three animals. This study provides evidence to suggest that cross-species immunization with cochlear antigens might produce a humoral response that can be associeted with inner ear pathologic change and sensorineural hearing lose. [ABSTRACT FROM AUTHOR]

The cochlear prosthesis is not applicable to patients who lack an implantable cochlea or an intact vestibulocochlear nerve. Direct electrical stimulation of the cochlear nucleus (CN) of the brain stem might provide a method for auditory rehabilitation of these patients. A penetrating CN electrode has been developed and tissue tolerance to this device demonstrated. This study was undertaken to evaluate metabolic activation of central nervous system (CNS) auditory tracts produced by such implants. Regional cerebral glucose use resulting from CN stimulation was estimated in a series of chronically implanted guinea pigs with the use of [14C]−2-deoxyglucose (2-DG). Enhanced 2-DG uptake was observed in structures of the auditory tract. The activation of central auditory structures achieved with CN stimulation was similar to that produced by acoustic stimulation and by electrical stimulation of the modiolar portion of the auditory nerve in control groups. An interesting banding pattern was observed in the inferior colliculus following CN stimulation, as previously described with acoustic stimulation. This study demonstrates that functional metabolic activation of central auditory pathways can be achieved with a penetrating CNS auditory prosthesis. [ABSTRACT FROM AUTHOR]