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

•SUN11602 mimicked the neuroprotective activity of bFGF/FGFR1 intracellular signaling.•SUN11602 induced the increased expression of calbindin D-28 k mRNA and protein.•Overexpression of calbindin D-28K by SUN11602 helped impaired neurons survive.•SUN11602 activated FGFR1 without affecting the extracellular domain of receptor.•SUN11602 demonstrated no cell proliferative activity of somatic cells, unlike bFGF.

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 125I-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.