title: Oleanolic acid ameliorates cognitive dysfunction caused by cholinergic blockade via TrkB-dependent BDNF signaling.
abstract: Oleanolic acid is a naturally occurring triterpenoid and is widely present in food and medicinal plants. To examine the effect of oleanolic acid on memory deficits, we employed a cholinergic blockade-induced cognitive deficit mouse model. A single administration of oleanolic acid significantly increased the latency on the passive avoidance task and affected the alternation behavior on the Y-maze task and the exploration time on the novel object recognition task, indicating that oleanolic acid reverses the cognitive impairment induced by scopolamine. In accordance with previous reports, oleanolic acid enhanced extracellular-signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Interestingly, ameliorating effect of oleanolic acid on scopolamine-induced memory impairment was abolished by N2-(2-{[(2-oxoazepan-3-yl)amino]carbonyl}phenyl)benzo[b]thiophene-2-carboxamide (ANA-12), a potent and specific inhibitor of tropomyosin receptor kinase B (TrkB), in the passive avoidance task. Similarly, oleanolic acid significantly evoked long-term potentiation in a dose-dependent manner, which was diminished by ANA-12 treatment as shown in the electrophysiology study. Together, these results imply that oleanolic acid ameliorates scopolamine-induced memory impairment by modulating the BDNF-ERK1/2-CREB pathway through TrkB activation in mice, suggesting that oleanolic acid would be a potential therapeutic agent for the treatment of cognitive deficits.
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Jeon
authors.affiliation: Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan 604-714, Republic of Korea.
authors.forename: Hong Ju
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Hyung Eun
authors.initials: HE
authors.lastname: Lee
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Yubeen
authors.initials: Y
authors.lastname: Gwon
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Haneul
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Jiabao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Seoul, 143-701, Republic of Korea.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.affiliation: Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan 604-714, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan 604-714, Republic of Korea. Electronic address: mose79@dau.ac.kr.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: jhryu63@khu.ac.kr.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Ryu
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D018680:Cholinergic Antagonists / Q000008:administration & dosage; D060825:Cognitive Dysfunction / Q000139:chemically induced / Q000378:metabolism* / Q000523:psychology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009828:Oleanolic Acid / Q000008:administration & dosage*; D020813:Receptor, trkB / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D012601:Scopolamine / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018680:Cholinergic Antagonists; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009828:Oleanolic Acid; D012601:Scopolamine; D020813:Receptor, trkB; D000109:Acetylcholine
keywords: BDNF signaling; Memory improvement; Oleanolic acid; Scopolamine model; TrkB