PMID- 28373010 OWN - NLM STAT- MEDLINE DCOM- 20170615 LR - 20211204 IS - 1873-6971 (Electronic) IS - 0367-326X (Linking) VI - 119 DP - 2017 Jun TI - Ecdysterones from Rhaponticum carthamoides (Willd.) Iljin reduce hippocampal excitotoxic cell loss and upregulate mTOR signaling in rats. PG - 158-167 LID - S0367-326X(16)30958-3 [pii] LID - 10.1016/j.fitote.2017.03.015 [doi] AB - Glutamate-induced excitotoxicity is a key pathological mechanism in many neurological disease states. Ecdysterones derived from Rhaponticum carthamoides (Willd.) Iljin (RCI) have been shown to alleviate glutamate-induced neuronal damage; although their mechanism of action is unclear, some data suggest that they enhance signaling in the mechanistic target of rapamycin (mTOR) signaling pathway. This study sought to elucidate the mechanisms underlying ecdysterone-mediated neuroprotection. We used in silico target prediction and simulation methods to identify putative ecdysterone binding targets, and to specifically identify those that represent nodes where several neurodegenerative diseases converge. We then used histological analyses in a rat hippocampal excitotoxicity model to test the effectiveness of ecdysterones in vivo. We found that RCI-derived ecdysterones should bind to glutamatergic NMDA-type receptors (NMDARs); specifically, in vivo modeling showed binding to the GRIN2B subunit of NMDARs, which was found also to be a node of convergence in several neurodegenerative disease pathways. Computerized network construction by using pathway information from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed putative links between GRIN2B and mTOR pathway elements including phosphoinositide-3kinase (PI3K), mTOR, and protein kinase C (PKC); these elements are associated with neuronal survival. Brain tissue western blots of ecdysterone-treated rats showed upregulated PI3K, Akt, mTOR, and phosphorylated Akt and mTOR, and down regulated GRIN2B and the apoptotic enzyme cleaved caspase-3. Ecdysterone treatment also prevented glutamate-induced rat hippocampal cell loss. In summary, RCI-derived ecdysterones appear to prevent glutamatergic excitotoxicity by increasing mTOR/Akt/PI3K signaling activity. CI - Copyright (c) 2017. Published by Elsevier B.V. FAU - Wu, Jiming AU - Wu J AD - School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Gao, Le AU - Gao L AD - School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Shang, Lei AU - Shang L AD - College of Basic Medical Science, Shenyang Medical College, Shenyang 110034, China. FAU - Wang, Guihua AU - Wang G AD - School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Wei, Nana AU - Wei N AD - School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Chu, Tiantian AU - Chu T AD - School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Chen, Suping AU - Chen S AD - School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Zhang, Yujun AU - Zhang Y AD - School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Huang, Jian AU - Huang J AD - School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: 13504051049@163.com. FAU - Wang, Jinhui AU - Wang J AD - School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; College of Pharmacy, Shihezi University, Shihezi 832002, China. Electronic address: 15999290001@163.com. FAU - Lin, Ruichao AU - Lin R AD - School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Traditional Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China. Electronic address: linrch307@sina.com. LA - eng PT - Journal Article DEP - 20170402 PL - Netherlands TA - Fitoterapia JT - Fitoterapia JID - 16930290R RN - 0 (NR2B NMDA receptor) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 3KX376GY7L (Glutamic Acid) RN - 5289-74-7 (Ecdysterone) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.22.- (Casp3 protein, rat) RN - EC 3.4.22.- (Caspase 3) SB - IM MH - Animals MH - Caspase 3/metabolism MH - Ecdysterone/isolation & purification/*pharmacology MH - Glutamic Acid/pharmacology MH - Hippocampus/cytology/*drug effects MH - Leuzea/*chemistry MH - Male MH - Molecular Docking Simulation MH - Molecular Dynamics Simulation MH - Molecular Structure MH - Neuroprotective Agents/isolation & purification/*pharmacology MH - Phosphorylation MH - Plant Roots/chemistry MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Signal Transduction/*drug effects MH - TOR Serine-Threonine Kinases/*metabolism MH - Up-Regulation OTO - NOTNLM OT - Computational simulation OT - Ecdysterones OT - GRIN2B OT - Neuroprotective OT - Rhaponticum carthamoides EDAT- 2017/04/05 06:00 MHDA- 2017/06/16 06:00 CRDT- 2017/04/05 06:00 PHST- 2016/12/14 00:00 [received] PHST- 2017/03/24 00:00 [revised] PHST- 2017/03/30 00:00 [accepted] PHST- 2017/04/05 06:00 [pubmed] PHST- 2017/06/16 06:00 [medline] PHST- 2017/04/05 06:00 [entrez] AID - S0367-326X(16)30958-3 [pii] AID - 10.1016/j.fitote.2017.03.015 [doi] PST - ppublish SO - Fitoterapia. 2017 Jun;119:158-167. doi: 10.1016/j.fitote.2017.03.015. Epub 2017 Apr 2.