Clinical application of neurotrophic factors: the potential for primary auditory neuron protection

Abstract

Sensorineural hearing loss, as a result of damage to or destruction of the sensory epithelia within the cochlea, is a common cause of deafness. The subsequent degeneration of the neural elements within the inner ear may impinge upon the efficacy of the cochlear implant. Experimental studies have demonstrated that neurotrophic factors can prevent this degeneration in animal models of deafness, and can even provide functional benefits. Neurotrophic factor therapy may, therefore, provide similar protective effects in humans, resulting in improved speech perception outcomes among cochlear implant patients. There are, however, numerous issues pertaining to delivery techniques and treatment regimes which need to be addressed prior to any clinical application. This review considers these issues in view of the potential therapeutic application of neurotrophic factors within the auditory system.

Survival and stimulation of neurite outgrowth in a serum-free culture of spiral ganglion neurons from adult mice

“…LIF has been known to enhance survival and neurite outgrowth in cultures derived from neonatal mice and rats (Gillespie et al, 2001;Marzella et al, 1997;Whitlon et al, 2006), but ours is the first report of a stimulatory effect on cultures derived from adult animals. BDNF and NTF3 have been shown previously to promote survival and neurite outgrowth upon ototoxic damage in vivo (Gillespie and Shepherd, 2005); in vitro, however, with spiral ganglion neurons from adult rats, they have been found to promote survival only (Lefebvre et al, 1994). In contrast, we observed in our cultures that BDNF stimulated both survival and neurite outgrowth; this discrepancy may have been due to the differences in age, species, and culture conditions.…”

“…To ascertain that the signaling pathways of the spiral ganglion neurons were not saturated by endogenous growth factors secreted from glial or other types of cells in our cultures and that survival and neurite outgrowth could be stimulated further by adding exogenous growth factors, we added BDNF, LIF, or NTF3 to the medium, each of which is known to protect cultured spiral ganglion neurons and stimulate neurite outgrowth (Gillespie and Shepherd, 2005). An initial dose-response analysis suggested optimal concentration ranges of 10-20 ng/ml for BDNF and NTF3, and 100-200 ng/ml for LIF (data not shown) that were consistent with previous reports (Lefebvre et al, 1994;Marzella et al, 1997;Mou et al, 1997;Whitlon et al, 2006;Zheng et al, 1995).…”

“…However, our understanding of the signaling events that underlie the survival of spiral ganglion neurons and the regeneration of their neurites is incomplete and requires further studies to guide technology development (Bianchi and Raz, 2004;Gillespie and Shepherd, 2005;Webber and Raz, 2006). The primary culture of dissociated spiral ganglion neurons from adult mice would be a useful addition to the experimental armamentarium for such studies.…”

Combining Cell-Based Therapies and Neural Prostheses to Promote Neural Survival

“…The use of mini-osmotic pumps in rodent deafness models, in which SGNs degenerate much more rapidly than in other species, such as the cat (in months [4]) and human (in years [19]), has limited the examination of NT therapies to relatively short timeframes. Furthermore, the limited reservoir and significant risk of infection associated with mini-pumps reduces their potential clinical application [20]. Consequently, the promise of NT therapy to rescue SGNs after SNHL has yet to be realized, and effective and safe drug administration strategies for application in the inner ear remains elusive.…”

The molecular basis of neurosensory cell formation in ear development: a blueprint for hair cell and sensory neuron regeneration?

“…(4,5) To maximize the viability of sensory neurons, several strategies are being explored using neurotrophin infusions. (6)(7)(8) Attempts are being made to understand the molecular mechanism that shuts down neurosensory proliferation in the ear through regulation of cyclin-dependent kinase inhibitor expression (9) in analogy to other systems. (10) Conceptually, it seems possible to translate those insights directly into reactivation of the dormant replacement capacity of mammals, comparable to the injury-induced regeneration of chicken hair cells.…”