Purpose: We evaluated the effects of the
drug MS-818 (2-piperadino-6-methyl-5-oxo-5,6-dihydro-(7H) pyrrolo-[3,4-d]
pyrimidine maleate), a synthesized
pyrimidine compound, on regeneration in crush-injured sciatic nerves of rats. Methods:
MS-818 at 1.0 or 10 mg/kg or the vehicle was intraperitoneally injected into rats daity. The pinch test (PT) was performed 5 days after the operation. Walking function recovery was assessed by the sciatic nerve functional index (SFI). Time-dependent changes in the levels of transcripts of
nerve growth factor (
NGF) and
apolipoprotein E (
ApoE) genes were monitored by RT-PCR.
NGF peptide levels retained in the crushed nerves of rats 5 days after surgery and in the culture medium of IMS32 cells, a mouse Schwann cell line, incubated for 24 h with high or low doses of
MS-818, were measured by
enzyme immunoassay. Results: The PT showed that
MS-818 injection promoted axonal elongation by 19.3 % compared to the vehicle injected control (n = 7, *p < 0.03). The SFIs 3 weeks after injection of
MS-818 at 1.0 mg/kg and 1 0 mg/kg were significantly increased to the control level (n = 5-6, **p < 0.006 and *p < 0.03, respectively). Injection of
MS-818 at 1.0 mg/kg induced
NGF gene expression more than twofold compared to that of the control at 5 to 6 days after surgery (n = 4).
NGF levels in crushed nerves after
MS-818 injection at 1.0 and 10 mg/kg tended to be higher than those of the vehicle-injected controls by approximately 20 %, although it did not reach statistical significance. Treatment of IMS32 cells with
MS-818 failed to give rise to
NGF overproduction and its secretion into the culture medium. Conclusions: These present evidences suggest that
MS-818 enhances functional recovery of damaged sciatic nerves by promoting axonal sprouting through indirect activation of Schwann cells and that local production of
NGF rnay be activated by
MS-818.