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As with other cranial nerves and many CNS neurons, primary auditory neurons degenerate as a consequence of loss of input from their target cells, the inner hair cells (IHCs). Electrical stimulation (ES) of spiral ganglion cells (SGCs) has been shown to enhance their survival. Glial cell line-derived neurotrophic factor (GDNF) has also been shown to increase survival of SGCs following IHC loss. In this study, the combined effects of the GDNF transgene delivered by adenoviral vectors (Ad-GDNF) and ES were tested on SGCs after first eliminating the IHCs. Animal groups received Ad-GDNF or ES or both. Ad-GDNF was inoculated into the cochlea of guinea pigs after deafening, to overexpress human GDNF. ES-treated animals were implanted with a cochlear implant electrode and chronically stimulated. A third group of animals received both Ad-GDNF and ES (GDNF/ES). Electrically evoked auditory brainstem responses were recorded from ES-treated animals at the start and end of the stimulation period. Animals were sacrificed 43 days after deafening and their ears prepared for evaluation of IHC survival and SGC counts. Treated ears exhibited significantly greater SGC survival than nontreated ears. The GDNF/ES combination provided significantly better preservation of SGC density than either treatment alone. Insofar as ES parameters were optimized for maximal protection (saturated effect), the further augmentation of the protection by GDNF suggests that the mechanisms of GDNF- and ES-mediated SGC protection are, at least in part, independent. We suggest that GDNF/ES combined treatment in cochlear implant recipients will improve auditory perception. These findings may have implications for the prevention and treatment of other neurodegenerative processes. ., (Copyright 2002 Wiley-Liss, Inc.)

Noise overstimulation will induce or influence intracellular molecular pathways in the cochlea. One of these is the 'classical' stress response pathway involving heat shock proteins. Hsp70 is induced in the cochlea by a wide variety of stresses including noise, hyperthermia and ototoxic drugs. When a stress that induces Hsp70 is applied to the cochlea, there is protection from a subsequent noise that would normally cause a permanent hearing loss. An upstream regulator of heat shock protein transcription, heat shock factor 1, is expressed in the cochlea and activated by stress. Mice lacking this heat shock factor have reduced recovery from noise-induced hearing loss. The same noise exposure that induces Hsp70 also increases the level of glial cell line-derived neurotrophic factor in the cochlea. Moreover, when this neurotrophic factor is applied into the perilymph of scala tympani prior to a noise exposure there is a significant reduction in hair cell loss and hearing loss. With the potential for activation of multiple pathways in the response to noise, gene microarrays can be useful to examine global gene expression. Initial studies examined differential gene expression immediately following a mild noise exposure (from which there is complete recovery) versus an intense noise (giving profound permanent deafness). Differential expression of several immediate early genes was found following the intense but not the mild noise exposure., (Copyright 2002 S. Karger AG, Basel)

Deafness, with loss of sensory (hair) cells, results in progressive pathophysiological changes ending in the degeneration of most auditory nerve neurons. It is now possible to consider these events in the broader context of anti-apoptotic survival factors in the peripheral and central nervous system. One consequence of deafferentation of a neuron is the loss of neurotrophins that can lead to a change in oxidative state (formation of free radicals), changes in intracellular Ca(2+), and an up-regulation of apoptotic genes. Interventions that can modify availability of neurotrophins, [Ca(2+)](I), and/or free radical formation or their destructive effects, may preserve the auditory nerve. Some interventions (neurotrophins) may also lead to a regrowth of neurites. Studies in this area are of basic value and also of immediate clinical interest for the application of the cochlear prosthesis to the severe and profoundly deaf, since the benefits of this prosthesis are directly dependent on auditory nerve survival and the proximity of stimulating electrode to neuron. We, and others, have found that auditory nerve degeneration can be prevented by chronic electrical stimulation. We have demonstrated in vivo that this effect can be blocked by tetrodotoxin, thus indicating that propagated action potentials are a necessary condition, and by verapamil (Ca(2+) channel blocker), supporting in vitro studies by others, indicating that L-type Ca(2+) channels are necessary for stimulation-induced rescue of the deafferented auditory nerve. The intensities of electrical stimulation required for rescue are at levels sufficient to express the intermediate-early gene c-fos which can initiate transcription of anti-apoptotic genes and pathways, and up-regulate expression of neurotrophins that may act in an autocrine manner to protect the nerve from death. We, and others, have found that chronic local delivery (osmotic pump and microcannulation of the inner ear fluid spaces) of individual neurotrophins and cocktails of factors can also enhance survival of the deafferented nerve, and some can also initiate a regrowth of degenerated peripheral processes of the nerve into the region of the destroyed sensory epitheliae. Recently, we have shown that this rescue can occur with delayed intervention, after degeneration of some neurons has begun, more closely mimicking the human clinical situation. Finally, we have shown that interventions with antioxidants may also be effective in preventing pathophysiological changes of the auditory nerve following deafness. These studies in the auditory periphery support the 'neurotrophic factor hypothesis' as proposed as a general mechanism underlying neurodegenerative and age-related pathology of the central nervous system. Additional animal studies can yield a rational scientific basis to justify human trials, with a goal to maintain auditory cell survival and initiate and direct fiber growth to the next generation of prosthesis. Intimate contact between electrode and a dense population of auditory neurons should greatly enhance the benefits of these devices for the profoundly deaf., (Copyright 2002 S. Karger AG, Basel)

High-throughput DNA microarray technology allows for the assessment of large numbers of genes and can reveal gene expression in a specific region, differential gene expression between regions, as well as changes in gene expression under changing experimental conditions or with a particular disease. The present study used a gene array to profile normal gene expression in the rat whole cochlea, two subregions of the cochlea (modiolar and sensorineural epithelium), and the cochlear nucleus and inferior colliculus of the auditory brainstem. The hippocampus was also assessed as a well-characterized reference tissue. Approximately 40% of the 588 genes on the array showed expression over background. When the criterion for a signal threshold was set conservatively at twice background, the number of genes above the signal threshold ranged from approximately 20% in the cochlea to 30% in the inferior colliculus. While much of the gene expression pattern was expected based on the literature, gene profiles also revealed expression of genes that had not been reported previously. Many genes were expressed in all regions while others were differentially expressed (defined as greater than a twofold difference in expression between regions). A greater number of differentially expressed genes were found when comparing peripheral (cochlear) and central nervous system regions than when comparing the central auditory regions and the hippocampus. Several families of insulin-like growth factor binding proteins, matrix metalloproteinases, and tissue inhibitor of metalloproteinases were among the genes expressed at much higher levels in the cochlea compared with the central nervous system regions.

Recent findings that glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), and transforming growth factor a can protect the auditory hair cells from acoustic trauma or aminoglycoside ototoxicity in vivo raise the question of whether other neurotrophic factors can also protect the hair cells in vivo. Fibroblast growth factor-2 (FGF-2) can protect hair cells from neomycin ototoxicity in vitro, and in vivo study has shown upregulation of FGF receptor-3 in the cochlea following noise exposure, suggesting that some FGF family members might play a role in protection or repair of the cochlea from damage. We therefore examined if FGF-1 and FGF-2 chronically delivered to the cochlea prior to noise overstimulation can attenuate noise-induced hair cell damage in vivo under conditions in which GDNF and NT-3 were effective. Pigmented female guinea pigs underwent left scala tympani implantation of a microcannula attached to an osmotic pump filled with artificial perilymph only or containing FGFs (10 or 1 mg/ml FGF-1 or 10 mg/ml FGF-2). They were exposed to noise (4 kHz octave band, 115 dB SPL, 5 hr) 4 days after surgery. Threshold shifts 10 days postexposure were essentially equivalent at all frequencies tested across different treatment groups. No significant difference in threshold shifts was observed between the treated and untreated ears in any of the groups. The extent of hair cell damage was also comparable among the different treatment groups. These findings indicate that exogenous FGF-1 or FGF-2 does not influence noise-induced hair cell damage under the experimental conditions used in this study, suggesting that these FGFs are not good candidates as auditory hair cell protectors in vivo.