The application of exogenous neurotrophins (NT) has been widely proposed as a therapeutic strategy for the recovery of regeneration in axotomised CNS neurons. Results from this approach have, however, been disappointing since limited regenerative responses are elicited, we suggest due to limited neurotrophin receptor (NTR) expression. NT exert their trophic effects by signalling through the Trk/p75 receptors. Adequate receptor expression levels must, therefore, be central to the capacity of CNS axons to regenerate in response to NT. We have compared the time-course of NTR mRNA expression in regenerating/non-regenerating CNS neuronal systems by ribonuclease protection assay. In the non-regenerating retinae levels of both full length (signalling) and truncated (non-signalling) variants of trkB and trkC decreased post-injury, recovering to those of controls by 20dpl. Reduced trk mRNA levels were also apparent at early post-injury time points in the regenerating retinae however at 20dpl these decreased levels were maintained and significantly lower compared to those in the non-regenerating model. By contrast, p75 mRNA levels rose modestly in the retinae after injury but were not significantly different between the regenerating and non-regenerating models. Similar results were observed in the DRG, axotomised either centrally (dorsal column lesion, non-regenerating) or peripherally (sciatic nerve crush, regenerating). Trk mRNA expression in the regenerating DRG was significantly lower than that in the non-regenerating. In this instance, p75 mRNA was also significantly reduced in the regenerating compared to non-regenerating DRG. These results highlight the importance of NTR levels in the regeneration response of axotomised neurons. We hypothesise that lower NTR mRNA levels observed in the regenerating systems versus non-regenerating may be a consequence of ligand-mediated down-regulation, and that this may be a significant factor limiting the regenerative capacity of NT-stimulated CNS neurons. The results suggest the potential usefulness of a NTR/NT gene delivery strategy for CNS repair.
22 - 24 Mar 2004
British Endocrine Societies