Flavonoids Induce the Expression of Synaptic Proteins, Synaptotagmin, and Postsynaptic Density Protein-95 in Cultured Rat Cortical Neuron

Abstract

Flavonoids, a family of phenolic compounds, are widely present in our daily diet and exist in traditional Chinese medicines, in which they act as the major active functional ingredients. Different lines of evidence indicate that flavonoids have positive impacts on human health. Here, different subclasses of flavonoids were analyzed for their inductive roles in promoting the expression of synaptic proteins, synaptotagmin, and post-synaptic density protein-95 in cultured rat cortical neurons. Among the screened 65 flavonoids, (−)-catechin, luteolin, and isorhamnetin, in micromolar concentration, were found to induce the expression of synaptic proteins in a dose-dependent manner: the induction values were from 2- to 8-fold that of the control. Similar results were revealed in the flavonoid-treated hippocampal neurons. The identification of these synapse-promoting flavonoids could be very useful in finding potential drugs, or food supplements, for treating various neurodegenerative diseases, including Alzheimerʼs disease and depression.

Key words

flavonoids - catechin - luteolin - isorhamnetin - synapse - synaptogenesis

• References

• 1 Miksicek RJ. Commonly occurring plant flavonoids have estrogenic activity. Mol Pharmacol 1993; 44: 37-43
• 2 Zhu JTT, Choi RCY, Chu GKY, Cheung AWH, Gao QT, Li J, Jiang ZY, Dong TTX, Tsim KWK. Flavonoids possess neuroprotective effects on cultured pheochromocytoma PC12 cells: a comparison of different flavonoids in activating estrogenic effect and in preventing β-amyloid-induced cell death. J Agric Food Chem 2007; 55: 2438-2445
• 3 Beecher GR. Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr 2003; 133: 3248S-3254S
• 4 Li Q, Zhao HF, Zhang ZF, Liu ZG, Pei XR, Wang JB, Li Y. Long-term green tea catechin administration prevents spatial learning and memory impairment in senescence-accelerated mouse prone-8 mice by decreasing Aβ1–42 oligomers and upregulating synaptic plasticity-related proteins in the hippocampus. Neuroscience 2009; 163: 741-749
• 5 Wang X, Zhang L, Hua L, Xing D, Du L. Effect of flavonoids in scutellariae radix on depression-like behavior and brain rewards: Possible in dopamine system. Tsinghua Sci Technol 2010; 15: 460-466
• 6 Zhu JTT, Choi RCY, Xie HQ, Zheng KYZ, Guo AJY, Bi CWC, Lau DTW, Li J, Dong TTX, Lau BWC, Chen JJ, Tsim KWK. Hibifolin, a flavonol glycoside, prevents β-amyloid-induced neurotoxicity in cultured cortical neurons. Neurosci Lett 2009; 461: 172-176
• 7 Choi RCY, Zhu JTT, Leung KW, Chu GKY, Xie HQ, Chen VP, Zheng KYZ, Lau DTW, Dong TTX, Chow PCY, Han YF, Wang ZT, Tsim KWK. A flavonol glycoside, isolated from roots of Panax notoginseng, reduces amyloid-β-induced neurotoxicity in cultured neurons: signaling transduction and drug development for Alzheimerʼs disease. J Alzheimers Dis 2010; 19: 795-811
• 8 Xu SL, Choi RCY, Zhu KY, Leung KW, Guo AJY, Bi D, Xu H, Lau DTW, Dong TTX, Tsim KWK. Isorhamnetin, a flavonol aglycone from Ginkgo biloba L., induces neuronal differentiation of cultured PC12 cells: Potentiating the effect of nerve growth factor. Evid Based Complement Alternat Med 2012; 2012: 278273
• 9 Murphy DD, Rueter SM, Trojanowski JQ, Lee VMY. Synucleins are developmentally expressed, and α-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 2000; 20: 3214-3220
• 10 Rowan MJ, Klyubin I, Wang Q, Hu NW, Anwyl R. Synaptic memory mechanisms: Alzheimerʼs disease amyloid β-peptide-induced dysfunction. Biochem Soc Trans 2007; 35: 1219-1223
• 11 Geppert M, Goda Y, Hammer RE, Li C, Rosahl TW, Stevens CF, Südhof TC. Synaptotagmin I: a major Ca²⁺ sensor for transmitter release at a central synapse. Cell 1994; 79: 717-727
• 12 Linden DJ, Ahn S. Activation of presynaptic cAMP-dependent protein kinase is required for induction of cerebellar long-term potentiation. J Neurosci 1999; 19: 10221-10227
• 13 Jorquera RA, Huntwork-Rodriguez S, Akbergenova Y, Cho RW, Troy Littleton JT. Complexin controls spontaneous and evoked neurotransmitter release by regulating the timing and properties of synaptotagmin activity. J Neurosci 2012; 50: 18234-18245
• 14 Xu B, Li XX, He GR, Hu JJ, Mu X, Tian S, Du GH. Luteolin promotes long-term potentiation and improves cognitive functions in chronic cerebral hypoperfused rats. Eur J Pharmacol 2010; 627: 99-105
• 15 Bastianetto S, Ramassamy C, Doré S, Christen Y, Poirier J, Quirion R. The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by β-amyloid. Eur J Neurosci 2000; 12: 1882-1890
• 16 Matsuzaki K, Kenichi M, Sakai S, Yawo H, Nakata N, Moriguchi S, Fukunaga K, Yokosuka A, Sashida Y, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y. Nobiletin, a citrus flavonoid with neurotrophic action, augments protein kinase A-mediated phosphorylation of the AMPA receptor subunit, GluR1, and the postsynaptic receptor response to glutamate in murine hippocampus. Eur J Pharmacol 2008; 578: 194-200
• 17 Spencer JPE. The interactions of flavonoids within neuronal signalling pathways. Genes Nutr 2007; 2: 257-273
• 18 Kretz O, Fester L, Wehrenberg U, Zhou L, Brauckmann S, Zhao S, Prange-Kiel J, Naumann T, Jarry H, Frotscher M, Rune GM. Hippocampal synapses depend on hippocampal estrogen synthesis. J Neurosci 2004; 24: 5913-5921
• 19 Siow NL, Choi RCY, Xie HQ, Kong LW, Chu GKY, Chan GKL, Simon L, Barnard EA, Tsim KWK. ATP induces synaptic gene expressions in cortical neurons: transduction and transcription control via P2Y 1 receptors. Mol Pharmacol 2010; 78: 1059-1071
• 20 Brewer GJ. Serum-free B27/neurobasal medium supports differentiated growth of neurons from the striatum, substantia nigra, septum, cerebral cortex, cerebellum, and dentate gyrus. J Neurosci Res 1995; 42: 674-683
• 21 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63
• 22 Zhang WL, Zheng KYZ, Zhu KY, Zhan JYX, Bi CWC, Chen JP, Du CYQ, Zhao KJ, Lau DTW, Dong TTX, Tsim KWK. Chemical and biological assessment of Angelica herbal decoction: comparison of different preparations during historical applications. Phytomedicine 2012; 19: 1042-1048
• 23 Winer J, Jung CKS, Shackel I, William PM. Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro . Anal Biochem 1999; 270: 41-49
• 24 Lee HHC, Choi RCY, Ting AKL, Siow NL, Jiang JXS, Massoulie J, Tsim KWK. Transcriptional regulation of acetylcholinesterase-associated collagen ColQ: differential expression in fast and slow twitch muscle fibers is driven by distinct promoters. J Biol Chem 2004; 279: 27098-27107