title: Berberine regulates neurite outgrowth through AMPK-dependent pathways by lowering energy status.
abstract: As a widely used anti-bacterial agent and a metabolic inhibitor as well as AMP-activated protein kinase (AMPK) activator, berberine (BBR) has been shown to cross the blood-brain barrier. Its efficacy has been investigated in various disease models of the central nervous system. Neurite outgrowth is critical for nervous system development and is a highly energy-dependent process regulated by AMPK-related pathways. In the present study, we aimed to investigate the effects of BBR on AMPK activation and neurite outgrowth in neurons. The neurite outgrowth of primary rat cortical neurons at different stages of polarization was monitored after exposure of BBR. Intracellular energy level, AMPK activation and polarity-related pathways were also inspected. The results showed that BBR suppressed neurite outgrowth and affected cytoskeleton stability in the early stages of neuronal polarization, which was mediated by lowered energy status and AMPK activation. Liver kinase B1 and PI3K-Akt-GSK3β signaling pathways were also involved. In addition, mitochondrial dysfunction and endoplasmic reticulum stress contributed to the lowered energy status induced by BBR. This study highlighted the knowledge of the complex activities of BBR in neurons and corroborated the significance of energy status during the neuronal polarization.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors.forename: Yuanzhao
authors.initials: Y
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors.forename: Kuoyuan
authors.initials: K
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors.forename: Tianchang
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Medicine, Children׳s Hospital Boston, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA. Electronic address: xudong.feng@childrens.harvard.edu.
authors.forename: Xudong
authors.initials: X
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, PR China. Electronic address: xqing@hsc.pku.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xia
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D008928:Mitochondria / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D001599:Berberine; D055372:AMP-Activated Protein Kinases; D002118:Calcium
keywords: AMPK; Berberine; Energy status; Neurite outgrowth