A synthesized pyrimidine compound, MS-818, promotes walking function recovery from crush injury of the sciatic nerve through its indirect stimulationof Schwann cells

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 rat s. Methods: MS-818 at 1.0 or 10 mg/kg or the vehicle was intraperitoneally inj ected into rats daily. The pinch test (PT) was performed 5 days after the o peration. Walking function recovery was assessed by the sciatic nerve funct ional index (SFI). Time-dependent changes in the levels of transcripts of n erve growth factor (NGF) and apolipoprotein E (ApoE) genes were monitored b y 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 cel l 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 SFI s 3 weeks after injection of MS-818 at 1.0 mg/kg and 10 mg/kg were signific antly increased to the control level (n = 5-6, **p < 0.006 and *p < 0.03, r espectively). 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 surg ery (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 b y approximately 20 %, although it did not reach statistical significance. T reatment of IMS32 cells with MS-818 failed to give rise to NGF overproducti on and its secretion into the culture medium. Conclusions: These present evidences suggest that MS-818 enhances functiona l recovery of damaged sciatic nerves by promoting axonal sprouting through indirect activation of Schwann cells and that local production of NGF may b e activated by MS-818.