Inhibition of connexin 43 induces hearing loss in postnatal mice

BackgroundConnexin 43 (Cx43) is the most ubiquitously expressed member of the family of connexins, constituting gap junctions and mediating cell communication, still its role in hearing loss has been little studied.MethodsImmunohistochemistry was used to detect the expression pattern of Cx43. Spiral ganglia neurons (SGNs) and Corti co-culture were utilized to assay the re-innervation of hair cells by newborn SGNs. Gap19 was utilized to inhibit Cx43 hemichannels. Auditory brainstem responses (ABR) and endocochlear potential (E.P.) were measured to confirm the hearing loss.ResultsThe expression of Cx43 in P14 mice was higher than in P0 and P28 (adult) mice, the earlier time point coinciding with the early inner ear development. Additionally, the growth and synapse generation of fibers were inhibited after Gap 19 treatment of the co-cultures of the Corti and SGNs from newborn mice. Furthermore, the inhibition of Cx43 could increase the ABR threshold and decrease E.P. level in postnatal mice, whereas such an effect was not observed in adult mice.ConclusionThe function of Cx43 is critical during the early development of mouse cochlea but is dispensable in adult mice.

Decellularized equine carotid artery layers as matrix for regenerated neurites of spiral ganglion neurons

Today’s best solution in compensating for sensorineural hearing loss is the cochlear implant, which electrically stimulates the spiral ganglion neurons in the inner ear. An optimum hearing impression is not ensured due to, among other reasons, a remaining anatomical gap between the spiral ganglion neurons and the implant electrodes. The gap could be bridged via pharmacologically triggered neurite growth toward the electrodes if biomaterials for neurite guidance could be provided. For this, we investigated the suitability of decellularized tissue. We compared three different layers (tunica adventitia, tunica media, and tunica intima) of decellularized equine carotid arteries in a preliminary approach. Rat spiral ganglia explants were cultured on decellularized equine carotid artery layers and neurite sprouting was assessed quantitatively. Generally, neurite outgrowth was possible and it was most prominent on the intima (in average 83 neurites per spiral ganglia explants, followed by the adventitia (62 neurites) and the lowest growth on the media (20 neurites). Thus, decellularized equine carotid arteries showed promising effects on neurite regeneration and can be developed further as efficient biomaterials for neural implants in hearing research.

Functional Pattern of Increasing Concentrations of Brain-Derived Neurotrophic Factor in Spiral Ganglion: Implications for Research on Cochlear Implants

BACKGROUND: As previously various studies have suggested application of brain-derived neurotrophic factor (BDNF) may be considered as a promising future therapy for hearing deficits, in particular for the improvement of cochlear neurone loss during cochlear implantation.AIM: The present study's aim was to establish the upper threshold of the concentration of BDNF in Naval Medical Research Institute (NMRI) mice spiral ganglion outgrowth.METHODS: Spiral ganglion explants were prepared from post-natal day 4 (p4) (NMRI) mice of both sexes under the approval and guidelines of the regional council of Hearing Research Institute Tubingen.RESULTS: Spiral ganglion explants were cultured at postnatal days 4 in the presence of different concentrations of BDNF as described under methods. We chose an age of postnatal day (P4) and concentrations of BDNF 0; 6; 12.5; 25 and 50 ƞg/ml. Averaged neurite outgrowth is measured in 4 different cultures that were treated with different concentrations. Results show that with increasing concentrations of BDNF, the neurite density increases.CONCLUSION: The present finding show evidence that BDNF has a clear incremental effect on the number of neurites of spiral ganglia in the prehearing organ, but less on the neurite length. The upper threshold of exogenous BNDF concentration on spiral ganglion explant is 25 ƞg/ml. This means that concentration beyond this level has no further incremental impact. Therefore our suggestion for hydrogel concentration in NMRA mice in future research should be 25 ƞg/ml.

Modiolus-Hugging Intracochlear Electrode Array with Shape Memory Alloy

In the cochlear implant system, the distance between spiral ganglia and the electrodes within the volume of the scala tympani cavity significantly affects the efficiency of the electrical stimulation in terms of the threshold current level and spatial selectivity. Because the spiral ganglia are situated inside the modiolus, the central axis of the cochlea, it is desirable that the electrode array hugs the modiolus to minimize the distance between the electrodes and the ganglia. In the present study, we propose a shape-memory-alloy-(SMA-) embedded intracochlear electrode which gives a straight electrode a curved modiolus-hugging shape using the restoration force of the SMA as triggered by resistive heating after insertion into the cochlea. An eight-channel ball-type electrode array is fabricated with an embedded titanium-nickel SMA backbone wire. It is demonstrated that the electrode array changes its shape in a transparent plastic human cochlear model. To verify the safe insertion of the electrode array into the human cochlea, the contact pressures during insertion at the electrode tip and the contact pressures over the electrode length after insertion were calculated using a 3D finite element analysis. The results indicate that the SMA-embedded electrode is functionally and mechanically feasible for clinical applications.

Is halofantrine ototoxic? Experimental study on guinea pig cochlea model

Introduction:Halofantrine is a newly developed antimalarial drug used for the treatment of Plasmodium falciparum malaria. The introduction of this drug has been delayed because of its possible side effects, and due to insufficient studies on adverse reactions in humans. There have been no studies investigating its effect on hearing.Methods:Thirty guinea pigs were divided into three groups: a control group, a halofantrine therapeutic dose group and a halofantrine double therapeutic dose group. One cochlea specimen from each animal was stained with haematoxylin and eosin and the other with toluidine blue.Results:No changes were detected in the control group. The halofantrine therapeutic dose group showed loss and distortion of inner hair cells and inner phalangeal cells, and loss of spiral ganglia cells. In the halofantrine double therapeutic dose group, the inner and outer hair cells were distorted and there was loss of spiral ganglia cells.Conclusion:Halofantrine has mild to moderate pathological effects on cochlea histology, and can be considered an ototoxic drug.