Scabronine G Methyl Ester Improves Memory-Related Behavior and Enhances Hippocampal Cell Proliferation and Long-Term Potentiation via the BDNF-CREB Pathway in Olfactory Bulbectomized Mice.

Osamu Nakagawasai,Kohei Takahashi,Wataru Nemoto,Shigeki Moriguchi,Masahisa Nakada,Yu Kobayakawa,Jia-Rong Lin,Takayo Odaira,Kohji Fukunaga,Koichi Tan-No,Yasushi Yabuki

doi:10.3389/fphar.2020.583291

Abstract

A previous study reported that scabronine G methyl ester (SG-ME) potentially enhances the in vitro secretion of neurotrophic factors such as nerve growth factor via the protein kinase C (PKC)-ζ pathway. However, it remains unknown whether SG-ME can improve cognitive dysfunctions in olfactory bulbectomized (OBX) mice. To address this question, we evaluated SG-ME-treated and untreated OBX mice in a passive avoidance test. We also investigated potential effects of SG-ME on several parameters: cell proliferation and cAMP response element-binding protein (CREB) phosphorylation in the hippocampal dentate gyrus by immunohistochemistry, brain-derived neurotrophic factor (BDNF) levels in the hippocampus by Western blotting, p-CREB levels in the hippocampus by MapAnalyzer, and long-term potentiation (LTP) by electrophysiology. On the 14th day after surgery OBX mice showed altered passive avoidance and decreases in both cell proliferation and long-term potentiation in the hippocampus, while these changes were reversed by SG-ME (20 μg/mouse) 24 h after the treatment. The improvement in memory deficits was prevented when SG-ME was co-administeredwith either zeta inhibitory peptide (PKC-ζ inhibitor), anti-BDNF antibody, ANA-12 (TrkB antagonist), U0126 (MEK inhibitor), H-89 (PKA inhibitor), LY294002 (PI3K inhibitor) or KN-93 (CaMKII inhibitor). We found that SG-ME enhanced brain-derived neurotrophic factor and p-CREB levels in the hippocampus while p-CREB was localized in neurons, but not in astrocytes nor microglial cells. These findings revealed the potential of SG-ME in improving memory impairments by enhancing cell proliferation and LTP via activation of the BDNF/CREB signaling pathway in neurons.

Highlights

An association between olfactory and psychic functions has been previously reported (Sohrabi et al, 2012)
We evaluated the antidementia effect of scabronine G methyl ester (SG-ME) using the passive avoidance test
The present study revealed that Scabronine G (SG)-ME improves the memory impairment in OBX mice 24 h but not 30 min after its i.c.v. administration at a dose of 20 μg/mouse [Figures 1B,C], while no effect was observed in sham mice treated with SG-ME (Supplementary Figure S1)

Summary

Introduction

An association between olfactory and psychic functions has been previously reported (Sohrabi et al, 2012). The OBX mice showed diminished newborn neurons in the dentate gyrus (DG) of the hippocampus (Nakagawasai et al, 2016; Takahashi et al, 2018b). These abnormal behaviors and pathological changes in OBX rodents were rescued by antidementia drugs or chronic administration of antidepressant drugs (Saitoh et al, 2007; Yabuki et al, 2017; Takahashi et al, 2018b). Studies on the regulation of cell proliferation in the hippocampal DG of OBX mice could lead to therapeutic strategies against cognitive dysfunctions and depression

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Results

Conclusion