A novel neurotrophic pyrimidine compound MS-818 enhances neurotrophic effects of basic fibroblast growth factor.
MS-818 (2-piperadino-6-methyl-5-oxo-5, 6-dihydro (7H) pyrrolo [2,3-d]pyrimidine maleate), a newly synthesized heterocyclic pyrimidine derivative, promotes neurite outgrowth in neuronal cell lines. The survival-promoting effect of MS-818 on cultured neurons isolated from mouse cortices was examined. MS-818 promoted neuronal survival by inhibiting apoptosis in a dose-dependent manner. MS-818 treatment also activated mitogen-activated protein kinase (MAPK) of the extracellular signal regulation kinase 2, as demonstrated by Western blot analysis. The MAPK activation level in the cultures treated with MS-818 was almost equivalent to that in cultures treated with nerve growth factor but was less than that in cultures treated with epidermal growth factor and basic fibroblast growth factor (bFGF). MAPK was activated within 3 min after the addition of MS-818, and its activity level returned to baseline within 120 min. Its activation was protein kinase C independent. We further investigated the effect of concurrent treatment with MS-818 and bFGF on neuronal survival. MS-818 enhanced the neuronal survival-promoting effect of bFGF in shifting the half-maximally effective dose from 2.1 ng/ml to 0.036 ng/ml in the sigmoidal dose effect of bFGF and permitted nearly maximum MAPK activation. The enhancement by MS-818 of the neuronal survival-promoting effect of bFGF was accompanied by sustained activation of MAPK to a degree that far exceeded, in magnitude and duration, the cooperative effect of MS-818 and bFGF. These results indicate that MS-818 promotes neuronal survival and enhances the neurotrophic actions of bFGF through stimulation of synchronous signals that may elevate MAPK levels within neurons.
Sanjo
N
N
Department of Neurology, Tokyo Medical and Dental University, School of Medicine, Japan.
Owada
K
K
Kobayashi
T
T
Mizusawa
H
H
Awaya
A
A
Michikawa
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003864:Depression, Chemical; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D011493:Protein Kinase C / Q000032:analysis; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
C096499:MS 818; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011743:Pyrimidines; D016222:Fibroblast Growth Factor 2; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases