SUN11602-induced hyperexpression of calbindin D-28k is pivotal for the survival of hippocampal neurons under neurotoxic conditions

• Published in: Brain research 2015-01, Vol.1594, p.71-81
• Main Authors: Murayama, Norihito, Noshita, Takafumi, Ogino, Ryoko, Masuda, Toyofumi, Kadoshima, Taisuke, Oka, Tetsushi, Ueno, Nobuhiro, Takemoto, Naohiro, Toba, Tetsuya, Ueno, Shinya, Schulze, Wiebke, Igawa, Yoshiyuki, Morita, Yasuhiro, Inoue, Teruyoshi
• Format: Article
• Language: English
• Subjects: Animals; Benzamides - pharmacology; Calbindin 1 - biosynthesis; Calbindin D-28k; Calcium homeostasis; Cell proliferation; Cell Survival - drug effects; FGF-2; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; Hippocampus - drug effects; Hippocampus - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurology; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neuroprotective Agents - pharmacology; Phenylenediamines - pharmacology; Polymerase Chain Reaction; Rats; Rats, Wistar; SUN11602
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2014.10.066

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 of125 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.