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Neuroprotective Effects of 3,6′-Disinapoyl Sucrose Through Increased BDNF Levels and CREB Phosphorylation via the CaMKII and ERK1/2 Pathway

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Abstract

3,6′-Disinapoyl sucrose (DISS) is an oligosaccharide ester natural product originating from the root of wild Polygala tenuifolia. Our previous reports suggested that DISS can have neuroprotective effects and antidepressive activity in rats, at least in part, by increased expression of cyclic AMP response element (CRE)-binding protein (CREB) and its downstream target protein, brain-derived neurotrophic factor (BDNF). The aim of the present study was to explore the mechanism of DISS-modulated BDNF and CREB expression. In this study, we confirmed its neuroprotective effect by showing that DISS, at concentrations above 30 μM, could promote the neuron cell viability and protected the glutamate and H2O2-induced toxicity in the human neuroblastoma (SH-SY5Y) cell line. DISS treatment also increased acute (from 15 to 30 min) BDNF expression and CREB phosphorylation in a dose-dependent manner. Pharmacological inhibition of mitogen-activated protein kinase 1 (ERK1/2), CaMKII, and Trk (with U0126, KN93, or K252a, respectively) partially attenuated the stimulatory effect of DISS on phospho-CREB and BDNF expression; however, it was not inhibited by pharmacological inhibition of PKA or PI3K (with H89 and LY294002, respectively). The results are consistent with the effects of DISS on CRE-directed gene transcription, as U0126 and KN-93 treatment also blocked the DISS-induced expression of the CRE-luciferase reporter gene. The results from the present study suggest that DISS-mediated regulation of BDNF gene expression is associated with CREB-mediated transcription of BDNF and upstream activation of ERK1/2 and CaMKII. Finally, DISS may exert neuroprotective and antidepressant effects through these signaling pathways in neuronal cells.

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Abbreviations

DISS:

3, 6′-Disinapoyl sucrose

CREB:

cAMP response element-binding protein

CRE:

cAMP response element

BDNF:

Brain-derived neurotrophic factor

PKA:

Protein kinase A

PI3K:

Phosphatidylinositol 3-kinase

TrkB:

Tropomyosin-related kinase B

CaM:

Calmodulin

CaMKII:

Calcium and calmodulin-dependent protein kinase

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

Akt:

Serine/threonine kinase

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Acknowledgments

This work was supported, in whole or in part, by the National Nature and Science Foundation of China (nos. 81173579 and 81173430).

Conflict of Interest

The authors had no financial or personal conflicts of interest.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Pharmacy Care Center, Chinese PLA General Hospital, No. 28 FuXing Road, Beijing, 100853, People’s Republic of China

    Yuan Hu, Ming-Yue Liu, Ping Liu & XianZhe Dong

  2. Department of Pharmacology and System Therapeutics, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Yuan Hu & Aislyn D. W. Boran

  3. Hebei North University, Zhangjiakou, Hebei, 075000, China

    Ming-Yue Liu

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  1. Yuan Hu
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  2. Ming-Yue Liu
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Correspondence to Ping Liu.

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Hu, Y., Liu, MY., Liu, P. et al. Neuroprotective Effects of 3,6′-Disinapoyl Sucrose Through Increased BDNF Levels and CREB Phosphorylation via the CaMKII and ERK1/2 Pathway. J Mol Neurosci 53, 600–607 (2014). https://doi.org/10.1007/s12031-013-0226-y

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