Graeme Clark Collection
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ItemExpression of the guidance molecule netrin-1 in the postnatal rat cochlea [Abstract]( nd)Purpose: Neurotrophic factors have been demonstrated to stimulate axonal growth from auditory neurons in both in vitro and in vivo animal models of deafness. These findings may be important to improving cochlear implant performance via an enhanced electro-neural interface, or ultimately for a regenerated auditory system. Numerous molecules exist which are involved in axon guidance during embryogenesis for the construction of a functional neural network. The netrins are a family of such guidance molecules, and are expressed within the developing cochlea. It remains to be determined, however, if these molecules are expressed in the developed mammalian cochlea, and therefore if they may be of potential use for guiding regenerated axons within the mammalian auditory system. This study seeks to investigate the expression patterns of the netrin-l protein in postnatal rats. Methods: Cochlear tissue samples were taken from rats at postnatal day I (PI), P3, P5, P7, Pl0, Pl5 and P22. Samples from each age group were separated using SDS-PAGE and protein expression was determined by western immunoblot analysis. Results: Preliminary findings suggest that the netrin-l protein may be present in the postnatal cochlea, however not in its full form. Spinal cord samples, used as positive controls, reveal an ~75kD immunoreactive band, consistent with the molecular weight (MW) of netrin-l. Cochlear samples displayed bands at a slightly lower MW, and may therefore represent proteolytic fragments of the full-length netrin-l protein. The signal showed decreasing intensity following P7, with no signal seen at P22. Conclusions: These results suggest that netrin-l may be present in the postnatal cochlea, and in decreasing levels with increasing age. Netrin-l may therefore have the potential to control new axonal growth in the adult mammalian cochlea. Further studies investigating the expression patterns of the netrin-l receptors, DCC and neogenin, will give a greater indication of the presence and role of this guidance cue within the damaged auditory system.
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ItemNeurotrophins support auditory neuron survival in vivo following an extended period of deafness [Abstract]( nd)Neurotrophic factors are important for the development and maintenance of the auditory system, and have also been reported to act as survival factors for auditory neurons in animal deafness models. Indeed, studies have demonstrated that application of neurotrophins into the inner ear shortly following deafening can prevent auditory neuron degeneration. However, little is known about the survival effects of delayed neurotrophin treatment, which is a clinically more realistic model. This study examined the capacity of various neurotrophins to support auditory neuron survival after an extended period of deafness in vivo. Specifically, we aimed to determine if the neurotrophins BDNF, NT-3, NT-4/5 and NGF could rescue neurons from degeneration after a two-week period of deafness. Normal hearing guinea pigs were bilaterally deafened; two weeks later the left cochleae were implanted with a mini-osmotic pump, which delivered 200µl of neurotrophin (62.5µg/ml) over a period of 28 days. The right cochleae acted as deafened and untreated internal controls. For all surgical procedures, guinea pigs were anaesthetised using ketamine (40mg/kg) and xylazil (4mg/kg). Delayed treatment with each of the four neurotrophins halted the degeneration of auditory neurons that is normally seen following loss of hair cells, resulting in neuronal survival rates of between 79-87% of normal hearing animals, as compared to only 52% survival in deafened, untreated controls. These results indicate that neurotrophins have the capacity to rescue auditory neurons from degeneration following an extended period of deafness. These findings suggest that neurotrophins may play a role as therapeutic agents in long-term deaf patients.