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.