A synthesized pyrimidine compound, MS-818, promotes walking
function recovery from crush injury of the sciatic nerve through its indirect
stimulation of Schwann cells
Affiliations: Department of Dynamic Pathology, Research Institute
for Neurological Disease and Geriatrics, Kyoto Prefectural University of
Medicine, Kyoto, Japan | Clinical Research Center, Utano National Hospital,
Kyoto, Japan | Institute of Biological Science, Mitsui
Pharmaceuticals, Inc., Tokyo, Japan
Note: [] Corresponding author: Ryuichi Fukuyama, Department of Dynamic
Pathology, Research Institute for Neurological Disease and Geriatrics. Kyoto
Prefectural University of Medicine, 465 Kawaramachi Hirokoji. Kamigyo-ku, Kyoto
602-0841, Japan. Tel.: +81 075 251 5849; Fax: +81 075 251 5849, E-mail:
[email protected]
Abstract: 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.
