title: SUN11602, a novel aniline compound, mimics the neuroprotective mechanisms of basic fibroblast growth factor.
abstract: Basic fibroblast growth factor (bFGF) offers some measure of protection against excitotoxic neuronal injuries by upregulating the expression of the calcium-binding protein calbindin-D28k (Calb). The newly synthesized small molecule 4-({4-[[(4-amino-2,3,5,6-tetramethylanilino)acetyl](methyl)amino]-1-piperidinyl}methyl)benzamide (SUN11602) mimics the neuroprotective effects of bFGF, and thus, we examined how SUN11602 exerts its actions on neurons in toxic conditions of glutamate. In primary cultures of rat cerebrocortical neurons, SUN11602 and bFGF prevented glutamate-induced neuronal death. This neuroprotection, which occurred in association with the augmented phosphorylation of the bFGF receptor-1 (FGFR-1) and the extracellular signal-regulated kinase-1/2 (ERK-1/2), was abolished by pretreatment with PD166866 (a FGFR-1 tyrosine kinase-specific inhibitor) and PD98059 (a mitogen-activated protein kinase [MAPK]/[ERK-1/2] kinase [MEK] inhibitor). In addition, SUN11602 and bFGF increased the levels of CALB1 gene expression in cerebrocortical neurons. Whether this neuroprotection was linked to Calb was investigated with primary cultures of cerebrocortical neurons from homozygous knockout (Calb(-/-)) and wild-type (WT) mice. In WT mice, SUN11602 and bFGF increased the levels of newly synthesized Calb in cerebrocortical neurons and suppressed the glutamate-induced rise in intracellular Ca(2+). This Ca(2+)-capturing ability of Calb allowed the neurons to survive severe toxic conditions of glutamate. In contrast, Calb levels remained unchanged in Calb(-/-) mice after exposure to SUN11602 or bFGF, and due to a loss of function of the gene, these neurons were no longer resistant to toxic conditions of glutamate. These findings indicated that SUN11602 activated a number of cellular molecules (FGFR-1, MEK/ERK intermediates, and Calb) and consequently contributed to intracellular Ca(2+) homeostasis as observed in the case of bFGF.
authors: Asubio Pharma Co., Ltd., Kobe 650-0047, Japan.
authors: Norihito
authors: N
authors: Murayama
authors: Taisuke
authors: T
authors: Kadoshima
authors: Naohiro
authors: N
authors: Takemoto
authors: Shiho
authors: S
authors: Kodama
authors: Tetsuya
authors: T
authors: Toba
authors: Ryoko
authors: R
authors: Ogino
authors: Takafumi
authors: T
authors: Noshita
authors: Tetsushi
authors: T
authors: Oka
authors: Shinya
authors: S
authors: Ueno
authors: Mariko
authors: M
authors: Kuroda
authors: Yoshiari
authors: Y
authors: Shimmyo
authors: Yasuhiro
authors: Y
authors: Morita
authors: Teruyoshi
authors: T
authors: Inoue
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D064092:Calbindin 1; D064026:Calbindins; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D018698:Glutamic Acid / Q000009:adverse effects*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010655:Phenylenediamines / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D064030:S100 Calcium Binding Protein G / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C584014:4-((4-(((4-amino-2,3,5,6-tetramethylanilino)acetyl)(methyl)amino)-1-piperidinyl)methyl)benzamide; D000814:Aniline Compounds; D001549:Benzamides; C576499:Calb1 protein, mouse; C576500:Calb1 protein, rat; D064092:Calbindin 1; D064026:Calbindins; D018696:Neuroprotective Agents; D010655:Phenylenediamines; D064030:S100 Calcium Binding Protein G; D016222:Fibroblast Growth Factor 2; D018698:Glutamic Acid; C496350:Fgfr1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3