Possible involvement of induction of brain-derived neurotrophic factor in the neuroprotective effect of a 5-phenylpyrimidine derivative.
When primary cortical neurons prepared from the brains of rat embryos (E18) were cultured in the absence of serum, most of the neurons died after 3 days in vitro. We used this model to discover compounds which support neuronal survival, and found that a new 5-phenylpyrimidine derivative named FU248 (2-amino-5-(2,4-dichlorophenyl) pyrimidine) inhibited the neuronal cell death in a dose-dependent manner up to 1 microg/mL. Semiquantitative RT-PCR analysis revealed that an exposure of the primary cortical neurons to 1 microg/mL of FU248 transiently and significantly enhanced the expression of genes including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3). The enhancement of the gene expression was maximal 6 hr after the addition of FU248, and the expression returned to the basal level after 24 hr. Expression of neurotrophin-4 was not detectable throughout the experimental period. The amount of the transcript for BDNF was approximately nine times and sixteen times more abundant than those for NT-3 and NGF, respectively (t=6 hr). Moreover, an anti-BDNF antibody suppressed the effect of FU248, whereas the control antibody did not show any effects on the neuronal survival. These findings strongly suggest that FU248 exerts its neuroprotective effect, at least in part, through induction of BDNF.
Matsumoto
Kayo
K
Molecular Biology Lab., Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Yoshino-cho 1-403, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
Yamamoto
Kyoko
K
Karasawa
Yasuko
Y
Hino
Noriko
N
Nakamura
Atsushi
A
Takahashi
Masayoshi
M
Araki
Hiroaki
H
Okuyama
Shigeru
S
Choshi
Tominari
T
Sugino
Eiichi
E
Hibino
Satoshi
S
Yoshimoto
Makoto
M
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology; D020869:Gene Expression Profiling; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats
C477899:2-amino-5-(2,4-dichlorophenyl) pyrimidine; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D011743:Pyrimidines; D020932:Nerve Growth Factor; C073922:neurotrophin 4