P. L. Marzella

BDNF-induced survival of auditory neurons in vivo: Cessation of treatment leads to accelerated loss of survival effects

Neurotrophic factors are important for the development and maintenance of the auditory system. They have also been shown to act as survival factors for auditory neurons in animal deafness models. Studies have demonstrated recently that these neurotrophic factors not only maintain survival of auditory neurons, but that these surviving neurons retain functionality. It remains to be determined, however, if a single administration of a neurotrophic factor is sufficient to maintain auditory neuron survival after loss of hair cells, or if sustained delivery is required. This study investigated the longevity of the survival effects of BDNF on auditory neurons in deafened guinea pigs. Briefly, the left cochleae of deafened guinea pigs were infused with BDNF for 28 days via a mini‐osmotic pump, and neuronal survival was analyzed at various stages after the completion of treatment. BDNF treatment prevented the degeneration of auditory neurons that normally is seen after a loss of hair cells, supporting previous studies. Our results indicate, however, that cessation of BDNF treatment leads to an accelerated decline in auditory neuron survival as compared to that observed in deafened, untreated cochleae. These findings indicate that much work remains to be done to establish a technique for the long‐term survival of auditory neurons in the deaf ear.

Delayed neurotrophin treatment supports auditory neuron survival in deaf guinea pigs.

As key factors in the development and maintenance of the auditory system, neurotrophins can prevent auditory neuron degeneration when applied within three to five days of deafening. We tested each of the neurotrophins BDNF, NT-3, NT-4/5 and NGF for their ability to support auditory neuron survival following a two-week period of deafness in guinea pigs, when ∼15% auditory neuron degeneration has already occurred. Although delayed, the treatment with each neurotrophin prevented further degeneration with similar efficacy.

The neurotrophins act synergistically with LIF and members of the TGF-β superfamily to promote the survival of spiral ganglia neurons in vitro

A number of growth factor families have been implicated in normal inner ear development, auditory neuron survival and protection. Several growth factors, including transforming growth factor-beta5 (TGF-beta5) and TGF-beta3, neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were tested for their ability, individually or in combination, to promote auditory neuron survival in dissociated cell cultures of early rat post-natal spiral ganglion cells (SGCs). The results indicate that at discrete concentrations all growth factors act in an additive fashion and some in synergy when promoting neuronal survival. These findings support the hypothesis that growth factors from different families may be interdependent when sustaining neuronal integrity.

LIF is more potent than BDNF in promoting neurite outgrowth of mammalian auditory neurons in vitro

Neurotrophic factors are known to play a crucial role in the elongation and guidance of auditory nerve fibres to their targets within the organ of Corti. Maintenance of these neural connections following deafness would clearly influence the efficacy of therapies for hearing recovery. The growth factors leukaemia inhibitory factor (LIF), brain-derived neurotrophic factor (BDNF) and transforming growth factor-beta 5 (TGF-β5) were tested for their efficacy in promoting neurite outgrowth from dissociated cultures of early postnatal rat auditory neurons. Our results indicate that while BDNF enhances neurite outgrowth in a strong fashion, LIF is more potent; moreover, the combined administration of both factors has even greater neuritogenic capacities. TGF-β5, although neurotrophic, has no neuritogenic activity on cultured auditory neurons. LIF and BDNF may therefore be potential candidates when developing pharmacological therapies for hearing recovery.

Growth factors, auditory neurones and cochlear implants: a review.

The total number and the integrity of the auditory neurones available for stimulation govern the benefits that patients can derive from cochlear implants. Although electrical stimulation of the cochlea has been reported to promote auditory neuronal survival, this trophic effect is insufficient to regenerate de novo fibres. Hence, any agent that can maximize the number of, or regenerate functional auditory neurones would be of great benefit. Several studies have identified various growth factors crucial to the normal development of auditory neurones. In addition, in vitro studies have demonstrated that several growth factors are important for the maintenance, rescue and repair of adult auditory neurones. In vivo studies confirm the in vitro findings, reporting that specific growth factors are able to support auditory neuronal survival following injury or trauma, and in lower species growth factors have been associated with regenerating auditory neurones. In addition to their trophic actions, several growth factors have also been reported to affect ion channels thus the electrical response of neuronal fibres. Indeed, growth factors have been reported to enhance neuronal excitation and to improve the efficacy of synaptic transmission. Taken in concert, these effects suggest that exogenous growth factors delivered to the cochlea may improve the transmission of the electrical stimuli from the implanted electrode to the auditory pathway. Further studies are warranted to investigate how the adjunct delivery of growth factors with the cochlear implant may constitute a better treatment for hearing-impaired individuals.

LIF potentiates the NT-3-mediated survival of spiral ganglia neurones in vitro

THE survival of auditory neurones depends on the continued supply of trophic factors. Early postnatal spiral ganglion cells (SGC) in a dissociated cell culture were used as a model of auditory innervation to test the trophic factors leukaemia inhibitory factor (LIF) and neurotrophin-3 (NT-3) for their ability, individually or in combination, to promote neuronal survival. The findings suggest that LIF supports neuronal survival in a concentration-dependent manner. Moreover LIF potentiated NT-3-mediated spiral ganglion neuronal survival in a synergistic fashion.

Synergy between TGF-β3 and NT-3 to promote the survival of spiral ganglia neurones in vitro

Transforming growth factor-betas (TGF-betas) have been implicated in normal inner ear development and in promoting neuronal survival. Early rat post-natal spiral ganglion cells (SGC) in dissociated cell culture were used as a model of auditory innervation to test the trophic factors TGF-beta3 and neurotrophin-3 (NT-3) for their ability, individually or in combination, to promote neuronal survival. The findings from this study suggest that TGF-beta3 supports neuronal survival in a concentration-dependent manner. Moreover TGF-beta3 and NT-3-potentiated spiral ganglion neuronal survival in a synergistic fashion.

Netrin-1 as a guidance molecule in the postnatal rat cochlea

During synaptogenesis a number of growth factors and peptides control the guidance of auditory neuron (spiral ganglion neuron, SGN) axons to their target cells. Furthermore, evidence suggests that these factors exert their actions at discrete times and sites during development. This study demonstrates that the guidance molecule netrin-1 is expressed in the early postnatal rat cochlea, but shows decreasing expression with increasing age. These results suggest that netrin-1 may be involved in guiding axonal growth from SGNs for the onset of innervation, but is not required for maintenance of synaptic connections.

Role Of Trophic Factors In The Development, Survival And Repair Of Primary Auditory Neurons

1. Neurotrophic factors have been identified as crucial for the development of the auditory system and have also been proven to be important for continued survival and maintenance of auditory neural connections.