PMID- 26135675 OWN - NLM STAT- MEDLINE DCOM- 20160506 LR - 20191210 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 303 DP - 2015 Sep 10 TI - Harpagoside ameliorates the amyloid-beta-induced cognitive impairment in rats via up-regulating BDNF expression and MAPK/PI3K pathways. PG - 103-14 LID - S0306-4522(15)00583-7 [pii] LID - 10.1016/j.neuroscience.2015.06.042 [doi] AB - So far, no effective disease-modifying therapies for Alzheimer's disease (AD) aiming at protecting or reversing neurodegeneration of the disease have been established yet. The present work aims to elucidate the effect of Harpagoside (abbreviated HAR), an iridoid glycosides purified from the Chinese medicinal herb Scrophularia ningpoensis, on neurodegeneration induced by beta-amyloid peptide (Abeta) and the underlying molecular mechanism. Here we show that HAR exerts neuroprotective effects against Abeta neurotoxicity. Rats injected aggregated Abeta(1)(-)(4)(0) into the bilateral hippocampus displayed impaired spatial learning and memory ability in a Y-maze test and novel object recognition test, while HAR treatment ameliorated Abeta(1)(-)(4)(0)-induced behavioral deficits. Moreover, administration of HAR increased the expression levels of brain-derived neurotrophic factor (BDNF) and activated the extracellular-regulated protein kinase (ERK) and the phosphatidylinositol 3-kinase (PI3-kinase) pathways both in the cerebral cortex and hippocampus of the Abeta(1)(-)(4)(0)-insulted rat model. Furthermore, in cultured primary cortical neurons, Abeta(1)(-)(4)(2) induced significant decrease of choline acetyltransferase (ChAT)-positive neuron number and neurite outgrowth length, both of which were dose dependently increased by HAR. In addition, HAR pretreatment also significantly attenuated the decrease of cell viability in Abeta(1)(-)(4)(2)-injured primary cortical neurons. Finally, when K252a, an inhibitor of Trk tyrosine kinases, and a BDNF neutralizing antibody were added to the culture medium 2 h prior to HAR addition, the protective effect of HAR on Abeta(1)(-)(4)(2)-induced neurodegeneration in the primary cortical neuron was almost inhibited. Taken together, HAR exerting neuroprotection effect and ameliorating learning and memory deficit appears to be associated, at least in part, with up-regulation of BDNF content as well as activating its downstream signaling pathways, e.g., MAPK/PI3K pathways. It raises the possibility that HAR has potential to be a therapeutic agent against AD. CI - Copyright (c) 2015 IBRO. All rights reserved. FAU - Li, J AU - Li J AD - Research Laboratory of Cell Regulation, School of Medicine, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, China. FAU - Ding, X AU - Ding X AD - Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA. FAU - Zhang, R AU - Zhang R AD - Research Laboratory of Cell Regulation, School of Medicine, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, China. FAU - Jiang, W AU - Jiang W AD - Research Laboratory of Cell Regulation, School of Medicine, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, China. FAU - Sun, X AU - Sun X AD - Research Laboratory of Cell Regulation, School of Medicine, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, China. FAU - Xia, Z AU - Xia Z AD - Research Laboratory of Cell Regulation, School of Medicine, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, China. FAU - Wang, X AU - Wang X AD - Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA. FAU - Wu, E AU - Wu E AD - Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA. Electronic address: erxi.wu@ndsu.edu. FAU - Zhang, Y AU - Zhang Y AD - Research Laboratory of Cell Regulation, School of Medicine, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: zhangyongfang1@yahoo.com. FAU - Hu, Y AU - Hu Y AD - Research Laboratory of Cell Regulation, School of Medicine, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: yaerhu@shsmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150629 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Amyloid beta-Peptides) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Glycosides) RN - 0 (Neuroprotective Agents) RN - 0 (Peptide Fragments) RN - 0 (Pyrans) RN - 0 (amyloid beta-protein (1-41)) RN - 8KGS1DC5ZU (harpagoside) SB - IM MH - Alzheimer Disease/chemically induced/metabolism/*prevention & control MH - Amyloid beta-Peptides/toxicity MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cerebral Cortex/*drug effects/metabolism MH - Cholinergic Neurons/drug effects/metabolism MH - Cognition/*drug effects MH - Glycosides/*administration & dosage MH - Hippocampus/drug effects/metabolism MH - MAP Kinase Signaling System/*drug effects MH - Male MH - Neurons/drug effects/metabolism MH - Neuroprotective Agents/*administration & dosage MH - Peptide Fragments/toxicity MH - Pyrans/*administration & dosage MH - Rats MH - Rats, Sprague-Dawley MH - Recognition, Psychology/drug effects MH - Spatial Learning/drug effects MH - Up-Regulation OTO - NOTNLM OT - Alzheimer's disease OT - Abeta OT - brain-derived neurotrophic factor (BDNF) OT - learning and memory deficits OT - p-AKT OT - p-ERK1/2 EDAT- 2015/07/03 06:00 MHDA- 2016/05/07 06:00 CRDT- 2015/07/03 06:00 PHST- 2015/03/25 00:00 [received] PHST- 2015/05/18 00:00 [revised] PHST- 2015/06/22 00:00 [accepted] PHST- 2015/07/03 06:00 [entrez] PHST- 2015/07/03 06:00 [pubmed] PHST- 2016/05/07 06:00 [medline] AID - S0306-4522(15)00583-7 [pii] AID - 10.1016/j.neuroscience.2015.06.042 [doi] PST - ppublish SO - Neuroscience. 2015 Sep 10;303:103-14. doi: 10.1016/j.neuroscience.2015.06.042. Epub 2015 Jun 29.