Protection and regrowth of the auditory nerve after deafness: neurotrophins, antioxidants and depolarization are effective in vivo.
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.
Miller
Josef M
JM
University of Michigan, Kresge Hearing Research Institute, Ann Arbor, MI 48109-0506, USA. Josef@umich.edu
Miller
Amy L
AL
Yamagata
Takahiko
T
Bredberg
Goran
G
Altschuler
Richard A
RA
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000627:therapeutic use; D015220:Calcium Channels / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003056:Cochlear Nerve / Q000473:pathology* / Q000502:physiology*; D003638:Deafness / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006168:Guinea Pigs; D009414:Nerve Growth Factors / Q000378:metabolism; D012038:Regeneration / Q000502:physiology
D000975:Antioxidants; D019208:Brain-Derived Neurotrophic Factor; D015220:Calcium Channels; D009414:Nerve Growth Factors