Neuroprotective effects of 3,6'-disinapoyl sucrose through increased BDNF levels and CREB phosphorylation via the CaMKII and ERK1/2 pathway.
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.
Department of Clinical Pharmacology, Pharmacy Care Center, Chinese PLA General Hospital, No. 28 FuXing Road, Beijing, 100853, People's Republic of China.
Yuan
Y
Hu
Ming-Yue
MY
Liu
Ping
P
Liu
XianZhe
X
Dong
Aislyn D W
AD
Boran
D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D003373:Coumaric Acids / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013395:Sucrose / Q000031:analogs & derivatives* / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003373:Coumaric Acids; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013395:Sucrose; C546986:3,6'-disinapoylsucrose