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The treatment of choice for profound sensorineural hearing loss (SNHL) is direct electrical stimulation of spiral ganglion cells (SGC) via a cochlear implant (CI). The number and excitability of SGC seem to be critical for the success that can be achieved via CI treatment. However, SNHL is associated with degeneration of SGC. Long-term drug delivery to the inner ear for improving SGC survival may be achieved by functionalisation of CI electrodes with cells providing growth factors. Therefore, the capacity of brain-derived neurotrophic factor (BDNF)-secreting NIH3T3 cells grown on cylindrically shaped silicone elastomers (SE) to exert local and sustained neuroprotective effects was assessed in vitro and in vivo. An in vitro model to investigate adhesion and cell growth of lentivirally modified NIH3T3 cells synthesising BDNF on SE was established. The bioactivity of BDNF was characterised by co-cultivation of SGC with cell-coated SE. In addition, cell-coated SE were implanted into deafened guinea pigs. The recombinant NIH3T3 cells proliferated on silicone surfaces during 14 days of cultivation and expressed significantly increasing BDNF levels. Enhanced survival rates and neurite outgrowth of SGC demonstrated the bioactivity of BDNF in vitro. Implantation of SE with adhering BDNF-secreting NIH3T3 cells into the cochleae of systemically deafened guinea pigs induced a significant increase in SGC survival in comparison to SE without cell coating. Our data demonstrate a novel approach of cell-based long-term drug delivery to support SGC survival in vitro and in vivo. This therapeutic strategy--once transferred to cells suitable for clinical application--may improve CI performance., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Brain derived neurotrophic factor (BDNF) and transforming growth factor-beta (TGFbeta) subtypes have demonstrated their importance in cochlear functions. The aim of this study was to determine gene and protein expression patterns of BDNF, TGFbeta1/2 and their main receptors trkB and TGFbetaR1/R2 in the auditory nerve and inferior colliculus of normal hearing and deafened rats by reverse-transcriptase polymerase chain reaction and immunohistochemistry. Deafening was performed by cochlear injection of neomycin (10%). Significant gene expression changes were not found in the inferior colliculus after deafness; however, in the auditory nerve, BDNF, TGFbeta1 and TGFbetaR1 mRNA in particular were upregulated. Additionally, BDNF protein and the cytokines were found to be expressed in the auditory nerve after hair cell loss. These data indicate the importance of BDNF and TGFbeta1 as endogenous survival factors.

Nerve growth factors play key roles in spiral ganglion cells survival and excitability. Our aim was to determine gene expression patterns of glial cell line-derived neurotrophic factor family (GDNF) members and their receptors in the auditory nerve and inferior colliculus of deafened rats. The gene expression of GDNF, persephin, artemin and neurturin, and their receptors GFRalpha1, GFRalpha2, GFRalpha3 and Ret, was determined by semiquantitative reverse transcriptase-polymerase chain reaction using GAPDH expression as an internal standard. Following deafness, no significant changes in expression of GDNF family genes were found in inferior colliculus. In contrast, artemin, GDNF, GFRalpha1-3 and Ret RNA expression were strongly upregulated in the auditory nerve following deafness, indicating their importance in protecting the auditory nerve against cell damage.

Background: The phenotype of deafness and its mechanisms are morphologically and electrophysiologically well characterised. However, the molecular mechanisms and the consequences of deafness are poorly understood., Methods: In this study we investigated changes in gene expression profiles in subfractions of the cochlea and the colliculus inferior, a non-cochlear tissue, of normal and deafened (10 % Neomycin) rats using the gene-array-technology. RNA was prepared from modiolus (Mo) und sensorineural epithel/lateral wall (SnE/Lw) und Colliculus inferior (IC), reverse transcribed with gene specific primers, labeled with (32)P-dATP and hybridised with its complementary sequences of 1200 rat ESTs., Results: Similar gene expression profiles were detected in Mo- and SnE/Lw in normal as well in deafened rats differing significantly from those found in IC. In deafened animals differences in mRNA levels were determined in IC for 8 genes, in Mo für 17 genes and in SnE/Lw for 25 genes in comparison to those of normal rats. By using gene-arrays many genes described in the literature previously could be detected. Otherwise most of the genes found in the cochlea are unknown., Conclusions: The gene-array-technology is a valuable tool in otological research for gene expression analysis and, therefore, for comprehensive understanding of molecular processes in the inner ear. Furthermore gene screening for candidate genes could be a big step ahead in developing therapies of diseases of the inner ear.