title: SUN11602-induced hyperexpression of calbindin D-28k is pivotal for the survival of hippocampal neurons under neurotoxic conditions.
abstract: Basic fibroblast growth factor (FGF-2/bFGF) possesses neuroprotective activity and promotes cell proliferation. In this study, the novel synthetic compound 4-({4-[[(4-amino-2,3,5,6-tetramethylanilino)acetyl](methyl)amino]-1-piperidinyl}methyl)benzamide (SUN11602) exhibited neuroprotective activities similar to those of FGF-2 without promoting cell proliferation. In primary cultures of hippocampal neurons, stimulation with SUN11602 or FGF-2 increased calbindin D-28k (CalB) gene expression and prevented glutamate-induced neuronal death. These effects were abolished by pretreatment with PD166866 (FGF receptor 1 [FGFR1] tyrosine kinase-specific inhibitor). This indicated that FGFR1 activation and increased CalB expression were involved in SUN11602-mediated neuroprotection. However, receptor-binding assays revealed that unlike FGF-2, SUN11602 did not alter the binding of (125)I-labeled FGF-2 to FGFR1. To investigate the possible proliferative activity of SUN11602, we utilized BHK21 and SKN cells expressing endogenous FGFR1. FGF-2 promoted cell proliferation whereas SUN11602 did not. In in vivo studies, wild-type (WT) and CalB-deficient (CalB(-/-)) mice were injected with aggregated Aβ1-40 and ibotenate (NMDA receptor agonist) to severely damage the hippocampal tissue. Treatment with SUN11602 (orally) or FGF-2 (intraparenchymally) at the midpoint of Aβ1-40 and ibotenate injections prevented the hippocampal damage in WT mice, however this effect was abolished in CalB(-/-) mice. Thus, SUN11602 exerted protective effects on hippocampal neurons through activation of FGFR1 and increased CalB expression. Moreover, the neuroprotective effects of SUN11602 depended upon the various biological activities of FGF-2.
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan. Electronic address: murayama.norihito.rk@asubio.co.jp.
authors.forename: Norihito
authors.initials: N
authors.lastname: Murayama
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Noshita
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Ogino
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Toyofumi
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kadoshima
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Oka
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ueno
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Takemoto
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Toba
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueno
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Schulze
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Igawa
authors.affiliation: Laboratory of Physiology and Morphology, Faculty of Pharmacy, Yasuda Women's University, Hiroshima 731-0153, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Morita
authors.affiliation: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D064092:Calbindin 1 / Q000096:biosynthesis*; D002470:Cell Survival / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010655:Phenylenediamines / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar
chemical_list: C584014:4-((4-(((4-amino-2,3,5,6-tetramethylanilino)acetyl)(methyl)amino)-1-piperidinyl)methyl)benzamide; D001549:Benzamides; C576499:Calb1 protein, mouse; D064092:Calbindin 1; D018696:Neuroprotective Agents; D010655:Phenylenediamines; D016222:Fibroblast Growth Factor 2
keywords: Calbindin D-28k; Calcium homeostasis; Cell proliferation; FGF-2; Neuroprotection; SUN11602