CONICET | Buscador de Institutos y Recursos Humanos

Demyelination is one of the hallmarks of the Wallerian degeneration (WD) process and cell therapy is among the strategies under study to induce remyelination. Results from our group obtained in a reversible model of WD induced by the crush of the rat sciatic nerve demonstrated the spontaneous migration of endogenous or transplanted bone marrow mononuclear cells (BMMC) exclusively to the injured nerve. Once in the ipsilateral nerve, some BMMC colocalized with Schwann cell markers and nerve fiber markers, which accelerated the regeneration process. On the basis of these results, the aim of the present work was to evaluate whether prostaglandins (PGs), one of the molecules generated during the inflammatory process associated with the injury, is one of the signals involved in the migration and recruitment of BMMC to the demyelinated nerve. To that end, adult Wistar rats were submitted to sciatic nerve crush and one group of animals was transplanted with BMMC through the sacra artery immediately. The presence of BMMC in the injured nerve was evaluated through confocal microscopy 24 h, 3 and 5 days post injury; the expression of ciclooxigenase 2 (Cox-2) was evaluated at 24 and 72 h and the synthesis of PGs were evaluated between 0 and 24 h post crush, through Western blot and PGs radioconversion, respectively. Besides, the effect of a non-steroidal anti-inflammatory drug as indomethacin on the migration of BMMC and PGs biosynthesis was analyzed, treating the animals with a subcutaneous injection of indomethacin 50 mg/kg/day the day of the lesion and the previous day, and 5 mg/kg/day the subsequent days. The results obtained show that, as soon as 24 h post injury, BMMC arrived at the edges of the ipsilateral nerve, and after 3 days they became part of it. Our results demonstrate the biosynthesis of PGE2, PGD2 and PGJ2 in sciatic nerve homogenates, and that their levels did not change significantly as a consequence of the lesion. Although indomethacin inhibited the migration of transplanted BMMC to the injured sciatic nerve, the biosynthesis of PGE2 and PGD2 was not affected. Surprisingly, indomethacin promoted a significant increase in PGJ2 both in the contralateral and the ipsilateral nerves as well as in the control nerve. These increase is dose-dependent, as rats treated with 12.5 or 25 mg/kg showed a smaller increase in PGJ2 synthesis.In the light of these results we can suggest that indomethacin action on BMMC migration occurs through an independent PG-mediated mechanism such as the PPARɣ pathway. Further experiments are necessary to elucidate indomethacin effect on BMMC migration and on the degeneration-regeneration process.