| Abstract No.: | C-D3132 |
| Country: | Canada |
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| Title: | SYSTEMIC INCREASE OF CAMP BY ROLIPRAM ADMINISTRATION OR DEGRADATION OF PROTEOGLYCANS IN THE DISTAL STUMP IMPROVES PERIPHERAL MOTOR AXONAL REGENERATION IN RATS |
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| Authors/Affiliations: | 1 Tessa Gordon*; 1 Matthew Furey; 1 Neil Tyreman; 2 Esther Udina;
1 Division of Physical Medicine and Rehabilitation, Faculty of Medicine and Dentistry, Division of Neurosciences, University of Alberta, Canada; 2 Physiology Unit, Faculty of Medicine and Institute of Neurosciences, Universitat Auṭnoma de Barcelona, Spain
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| Content: | Proteins associated with myelin and the proteoglycans of the extracellular matrix are well known inhibitors of central axon regeneration. This central inhibitory environment can be overcome by elevating cAMP in neurons or by degrading proteoglycans with the enzyme chondroitinase ABC (ChABC). Here we asked whether similar mechanisms operate in peripheral nerve regeneration where effective Wallerian degeneration only slowly removes myelin and the extracellular proteoglycans. We repaired the transected CP nerve in rats and elevated cAMP in the axotomized neurons by subcutaneous rolipram, a specific inhibitor of the phosphodiesterase IV and/or local application of ChABC to degrade proteoglycans in the distal stump. Homogenates from DRG and spinal cords from animals treated with rolipram showed a significant 2-fold increase in cAMP levels at 4d of treatment when compared with saline treated groups. At this time point, we could not observe that rolipram treatment accelerates Wallerian degeneration, since both saline and rolipram treated groups showed similar proportions of degenerating fibers in the distal stump (mean±SE of 67%±5). However, in the rolipram treated group there was a significant increase of myelinated regenerative fibers 2mm distal to the lesion site at 14d (765±152) when compared to the saline treated group (98±52). In another set of rats we backlabeled the regenerating axons that had crossed the suture site at 7 and 14 days. At 7d, we observed that rolipram treatment increased the number of motor (but not sensory) axons that crossed the suture site by 2-fold (33±9) when compared to the saline treated group (9.1±3). At 14d, all the axons in the rolipram treated group had crossed the suture site (343±27 versus 210±50 in the saline treated group). The number of motor axons that regenerated 10mm through the distal stump at 14 d was also significantly increased by rolipram treatment (194±22 versus 109±20 in the saline treated group). Local application of ChABC had the same effect of promoting motor axon regeneration 10mm distal to the suture site (180±20) as the rolipram treatment with the effect being no greater when rolipram and ChABC were administered simultaneously (202±34). We conclude that blocking inhibitors of axon regeneration by elevating cAMP and degrading proteoglycans in the distal nerve stump promote the peripheral axon regeneration after surgical repair of a transected nerve. Since there was no additive effect in the combined rolipram and ChABC treated group, it is likely that the effects of these two treatments are mediated through a common pathway. |
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