nach oben

NeuroMolecular Medicine

Erschienen in:

23.06.2016 | Original Paper

Botanical Polyphenols Mitigate Microglial Activation and Microglia-Induced Neurotoxicity: Role of Cytosolic Phospholipase A₂

verfasst von: Dennis Y. Chuang, Agnes Simonyi, Jiankun Cui, Dennis B. Lubahn, Zezong Gu, Grace Y. Sun

Erschienen in: NeuroMolecular Medicine | Ausgabe 3/2016

Einloggen, um Zugang zu erhalten

Abstract

Microglia play a significant role in the generation and propagation of oxidative/nitrosative stress, and are the basis of neuroinflammatory responses in the central nervous system. Upon stimulation by endotoxins such as lipopolysaccharides (LPS), these cells release pro-inflammatory factors which can exert harmful effects on surrounding neurons, leading to secondary neuronal damage and cell death. Our previous studies demonstrated the effects of botanical polyphenols to mitigate inflammatory responses induced by LPS, and highlighted an important role for cytosolic phospholipase A₂ (cPLA₂) upstream of the pro-inflammatory pathways (Chuang et al. in J Neuroinflammation 12(1):199, 2015. doi:10.1186/s12974-015-0419-0). In this study, we investigate the action of botanical compounds and assess whether suppression of cPLA₂ in microglia is involved in the neurotoxic effects on neurons. Differentiated SH-SY5Y neuroblastoma cells were used to test the neurotoxicity of conditioned medium from stimulated microglial cells, and WST-1 assay was used to assess for the cell viability of SH-SY5Y cells. Botanicals such as quercetin and honokiol (but not cyanidin-3-O-glucoside, 3CG) were effective in inhibiting LPS-induced nitric oxide (NO) production and phosphorylation of cPLA₂. Conditioned medium from BV-2 cells stimulated with LPS or IFNγ caused neurotoxicity to SH-SY5Y cells. Decrease in cell viability could be ameliorated by pharmacological inhibitors for cPLA₂ as well as by down-regulating cPLA₂ with siRNA. Botanicals effective in inhibition of LPS-induced NO and cPLA₂ phosphorylation were also effective in ameliorating microglial-induced neurotoxicity. Results demonstrated cytotoxic factors from activated microglial cells to cause damaging effects to neurons and potential use of botanical polyphenols to ameliorate the neurotoxic effects.

Aguzzi, A., Barres, B. A., & Bennett, M. L. (2013). Microglia: Scapegoat, saboteur, or something else? [Research Support, Non-US. Gov’t Review]. Science, 339(6116), 156–161. doi:10.1126/science.1227901.CrossRefPubMedPubMedCentral

Annapurna, A., Ansari, M. A., & Manjunath, P. M. (2013). Partial role of multiple pathways in infarct size limiting effect of quercetin and rutin against cerebral ischemia–reperfusion injury in rats. European Review for Medical and Pharmacological Sciences, 17(4), 491–500.PubMed

Biedler, J. L., Roffler-Tarlov, S., Schachner, M., & Freedman, L. S. (1978). Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones. Cancer Research, 38(11 Pt 1), 3751–3757.PubMed

Block, M. L., & Hong, J. S. (2005). Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism. Progress in Neurobiology, 76(2), 77–98. doi:10.1016/j.pneurobio.2005.06.004.CrossRef

Block, M. L., Zecca, L., & Hong, J. S. (2007). Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nature Reviews Neuroscience, 8(1), 57–69. doi:10.1038/nrn2038.CrossRefPubMed

Burke, J. E., & Dennis, E. A. (2009). Phospholipase A2 structure/function, mechanism, and signaling [Research Support, N.I.H., Extramural Review]. Journal of Lipid Research, 50(Suppl), S237–S242. doi:10.1194/jlr.R800033-JLR200.PubMedPubMedCentral

Calabrese, V., Cornelius, C., Dinkova-Kostova, A. T., Calabrese, E. J., & Mattson, M. P. (2010). Cellular stress responses, the hormesis paradigm, and vitagenes: Novel targets for therapeutic intervention in neurodegenerative disorders. Antioxidants & Redox Signaling, 13(11), 1763–1811. doi:10.1089/ars.2009.3074.CrossRef

Calder, P. C. (2008). The relationship between the fatty acid composition of immune cells and their function. Prostaglandins Leukotrienes and Essential Fatty Acids, 79(3–5), 101–108. doi:10.1016/j.plefa.2008.09.016.CrossRef

Chang-Mu, C., Jen-Kun, L., Shing-Hwa, L., & Shoei-Yn, L. S. (2010). Characterization of neurotoxic effects of NMDA and the novel neuroprotection by phytopolyphenols in mice [Research Support, Non-U.S. Gov’t]. Behavioral Neuroscience, 124(4), 541–553. doi:10.1037/a0020050.CrossRefPubMed

Chen, J. C., Ho, F. M., Pei-Dawn Lee, C., Chen, C. P., Jeng, K. C., Hsu, H. B., et al. (2005). Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia. European Journal of Pharmacology, 521(1–3), 9–20. doi:10.1016/j.ejphar.2005.08.005.CrossRefPubMed

Chen, H. H., Lin, S. C., & Chan, M. H. (2011). Protective and restorative effects of magnolol on neurotoxicity in mice with 6-hydroxydopamine-induced hemiparkinsonism. Neurodegener Disease, 8(5), 364–374. doi:10.1159/000323872.CrossRef

Chuang, D. Y., Chan, M. H., Zong, Y., Sheng, W., He, Y., Jiang, J. H., et al. (2013). Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Journal of Neuroinflammation, 10, 15. doi:10.1186/1742-2094-10-15.CrossRefPubMedPubMedCentral

Chuang, D. Y., Simonyi, A., Kotzbauer, P. T., Gu, Z., & Sun, G. Y. (2015). Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway. Journal of Neuroinflammation, 12(1), 199. doi:10.1186/s12974-015-0419-0.CrossRefPubMedPubMedCentral

Colton, C. A., & Gilbert, D. L. (1987). Production of superoxide anions by a CNS macrophage, the microglia. FEBS Letters, 223(2), 284–288.CrossRefPubMed

Galli, R. L., Shukitt-Hale, B., Youdim, K. A., & Joseph, J. A. (2002). Fruit polyphenolics and brain aging: Nutritional interventions targeting age-related neuronal and behavioral deficits [Review]. Annals of the New York Academy of Sciences, 959, 128–132.CrossRefPubMed

Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., & Gage, F. H. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell, 140(6), 918–934. doi:10.1016/j.cell.2010.02.016.CrossRefPubMedPubMedCentral

Gonzalez-Scarano, F., & Martin-Garcia, J. (2005). The neuropathogenesis of AIDS. Nature Reviews Immunology, 5(1), 69–81. doi:10.1038/nri1527.CrossRefPubMed

Huang, W., Bhavsar, A., Ward, R. E., Hall, J. C., Priestley, J. V., & Michael-Titus, A. T. (2009). Arachidonyl trifluoromethyl ketone is neuroprotective after spinal cord injury [Research Support, Non-U.S. Gov’t]. Journal of Neurotrauma, 26(8), 1429–1434. doi:10.1089/neu.2008-0835.CrossRefPubMed

Hwang, I. K., Lee, C. H., Yoo, K. Y., Choi, J. H., Park, O. K., Lim, S. S., et al. (2009). Neuroprotective effects of onion extract and quercetin against ischemic neuronal damage in the gerbil hippocampus. Journal of Medicinal Food, 12(5), 990–995. doi:10.1089/jmf.2008.1400.CrossRefPubMed

Jiang, J., Chuang, D. Y., Zong, Y., Patel, J., Brownstein, K., Lei, W., et al. (2014). Sutherlandia frutescens ethanol extracts inhibit oxidative stress and inflammatory responses in neurons and microglial cells [Research Support, N.I.H., Extramural]. PLoS ONE, 9(2), e89748. doi:10.1371/journal.pone.0089748.CrossRefPubMedPubMedCentral

Kang, C. H., Choi, Y. H., Moon, S. K., Kim, W. J., & Kim, G. Y. (2013). Quercetin inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-kappaB pathway and activating the Nrf2-dependent HO-1 pathway. International Immunopharmacology, 17(3), 808–813. doi:10.1016/j.intimp.2013.09.009.CrossRefPubMed

Kao, T. K., Ou, Y. C., Raung, S. L., Lai, C. Y., Liao, S. L., & Chen, C. J. (2010). Inhibition of nitric oxide production by quercetin in endotoxin/cytokine-stimulated microglia. Life Sciences, 86(9–10), 315–321. doi:10.1016/j.lfs.2009.12.014.CrossRefPubMed

Kaushik, D. K., Mukhopadhyay, R., Kumawat, K. L., Gupta, M., & Basu, A. (2012). Therapeutic targeting of Kruppel-like factor 4 abrogates microglial activation. Journal of Neuroinflammation, 9, 57. doi:10.1186/1742-2094-9-57.CrossRefPubMedPubMedCentral

Kuo, D. H., Lai, Y. S., Lo, C. Y., Cheng, A. C., Wu, H., & Pan, M. H. (2010). Inhibitory effect of magnolol on TPA-induced skin inflammation and tumor promotion in mice. Journal of Agriculture and Food Chemistry, 58(9), 5777–5783. doi:10.1021/jf100601r.CrossRef

La Quaglia, M. P., & Manchester, K. M. (1996). A comparative analysis of neuroblastic and substrate-adherent human neuroblastoma cell lines. Journal of Pediatric Surgery, 31(2), 315–318.CrossRefPubMed

Lee, J., Jo, D. G., Park, D., Chung, H. Y., & Mattson, M. P. (2014). Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: Focus on the nervous system. Pharmacological Reviews, 66(3), 815–868. doi:10.1124/pr.113.007757.CrossRefPubMedPubMedCentral

Lee, Y. J., Lee, Y. M., Lee, C. K., Jung, J. K., Han, S. B., & Hong, J. T. (2011). Therapeutic applications of compounds in the Magnolia family [Research Support, Non-U.S. Gov’t Review]. Pharmacology & Therapeutics, 130(2), 157–176. doi:10.1016/j.pharmthera.2011.01.010.CrossRef

Lee, S. C., Liu, W., Dickson, D. W., Brosnan, C. F., & Berman, J. W. (1993). Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. Journal of Immunol, 150(7), 2659–2667.

Leslie, C. C. (2015). Cytosolic phospholipase A2: Physiological function and role in disease. Journal of Lipid Research,. doi:10.1194/jlr.R057588.PubMedPubMedCentral

Liu, N. K., Deng, L. X., Zhang, Y. P., Lu, Q. B., Wang, X. F., Hu, J. G., et al. (2014). Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Annals of Neurology, 75(5), 644–658. doi:10.1002/ana.24134.CrossRefPubMedPubMedCentral

Liu, B., Gao, H. M., & Hong, J. S. (2003). Parkinson’s disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: Role of neuroinflammation. Environmental Health Perspectives, 111(8), 1065–1073.CrossRefPubMedPubMedCentral

Liu, B., Gao, H. M., Wang, J. Y., Jeohn, G. H., Cooper, C. L., & Hong, J. S. (2002). Role of nitric oxide in inflammation-mediated neurodegeneration. Annals of the New York Academy of Sciences, 962, 318–331.CrossRefPubMed

Liu, B., Hattori, N., Zhang, N. Y., Wu, B., Yang, L., Kitagawa, K., et al. (2005). Anxiolytic agent, dihydrohonokiol-B, recovers amyloid beta protein-induced neurotoxicity in cultured rat hippocampal neurons. Neuroscience Letters, 384(1–2), 44–47.CrossRefPubMed

Lull, M. E., & Block, M. L. (2010). Microglial activation and chronic neurodegeneration. Neurotherapeutics, 7(4), 354–365. doi:10.1016/j.nurt.2010.05.014.CrossRefPubMedPubMedCentral

Maruyama, Y., Kuribara, H., Morita, M., Yuzurihara, M., & Weintraub, S. T. (1998). Identification of magnolol and honokiol as anxiolytic agents in extracts of saiboku-to, an oriental herbal medicine. Journal of Natural Products, 61(1), 135–138.CrossRefPubMed

Oh, J. H., Kang, L. L., Ban, J. O., Kim, Y. H., Kim, K. H., Han, S. B., et al. (2009). Anti-inflammatory effect of 4-O-methylhonokiol, compound isolated from magnolia officinalis through inhibition of NF-kappaB [corrected]. Chemico-Biological Interactions, 180(3), 506–514. doi:10.1016/j.cbi.2009.03.014.CrossRefPubMed

Pan, X. D., Chen, X. C., Zhu, Y. G., Zhang, J., Huang, T. W., Chen, L. M., et al. (2008). Neuroprotective role of tripchlorolide on inflammatory neurotoxicity induced by lipopolysaccharide-activated microglia. Biochemical Pharmacology, 76(3), 362–372. doi:10.1016/j.bcp.2008.05.018.CrossRefPubMed

Ribeiro, R., Wen, J., Li, S., & Zhang, Y. (2013). Involvement of ERK1/2, cPLA2 and NF-kappaB in microglia suppression by cannabinoid receptor agonists and antagonists [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S.]. Prostaglandins & Other Lipid Mediators, 100–101, 1–14. doi:10.1016/j.prostaglandins.2012.11.003.CrossRef

Shen, S., Yu, S., Binek, J., Chalimoniuk, M., Zhang, X., Lo, S. C., et al. (2005). Distinct signaling pathways for induction of type II NOS by IFNgamma and LPS in BV-2 microglial cells. Neurochemistry International, 47(4), 298–307. doi:10.1016/j.neuint.2005.03.007.CrossRefPubMed

Sheng, W., Zong, Y., Mohammad, A., Ajit, D., Cui, J., Han, D., et al. (2011). Pro-inflammatory cytokines and lipopolysaccharide induce changes in cell morphology, and upregulation of ERK1/2, iNOS and sPLA(2)-IIA expression in astrocytes and microglia [Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural]. Journal of Neuroinflammation, 8, 121. doi:10.1186/1742-2094-8-121.CrossRefPubMedPubMedCentral

Simonyi, A., Chen, Z., Jiang, J., Zong, Y., Chuang, D. Y., Gu, Z., et al. (2015). Inhibition of microglial activation by elderberry extracts and its phenolic components. Life Sciences, 128, 30–38. doi:10.1016/j.lfs.2015.01.037.CrossRefPubMedPubMedCentral

Sun, G. Y., Chen, Z., Jasmer, K. J., Chuang, D. Y., Gu, Z., Hannink, M., et al. (2015). Quercetin attenuates inflammatory responses in BV-2 microglial cells: Role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS ONE, 10(10), e0141509. doi:10.1371/journal.pone.0141509.CrossRefPubMedPubMedCentral

Sun, A. Y., Wang, Q., Simonyi, A., & Sun, G. Y. (2008). Botanical phenolics and brain health. Neuromolecular Medicine, 10(4), 259–274. doi:10.1007/s12017-008-8052-z.CrossRefPubMedPubMedCentral

Sun, A. Y., Wang, Q., Simonyi, A., & Sun, G. Y. (2011). Botanical phenolics and neurodegeneration. In I. F. F. Benzie & S. Wachtel-Galor (Eds.), Herbal medicine: Biomolecular and clinical aspects (2nd ed.). Boca Raton, FL: CRC Press.

Vana, A. C., Li, S., Ribeiro, R., Tchantchou, F., & Zhang, Y. (2011). Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter [Research Support, Non-U.S. Gov’t]. Experimental Neurology, 231(1), 45–55. doi:10.1016/j.expneurol.2011.05.014.CrossRefPubMed

Wang, T., Pei, Z., Zhang, W., Liu, B., Langenbach, R., Lee, C., et al. (2005). MPP+-induced COX-2 activation and subsequent dopaminergic neurodegeneration. FASEB J, 19(9), 1134–1136. doi:10.1096/fj.04-2457fje.PubMed

Wang, S., Wang, H., Guo, H., Kang, L., Gao, X., & Hu, L. (2011). Neuroprotection of Scutellarin is mediated by inhibition of microglial inflammatory activation. Neuroscience, 185, 150–160. doi:10.1016/j.neuroscience.2011.04.005.CrossRefPubMed

Watanabe, K., Watanabe, H., Goto, Y., Yamaguchi, M., Yamamoto, N., & Hagino, K. (1983). Pharmacological properties of magnolol and honokiol extracted from Magnolia officinalis: Central depressant effects. Planta Medica, 49(2), 103–108.CrossRefPubMed

Wu, F., Zhang, W., Li, L., Zheng, F., Shao, X., Zhou, J., et al. (2011). Inhibitory effects of honokiol on lipopolysaccharide-induced cellular responses and signaling events in human renal mesangial cells [Research Support, Non-U.S. Gov’t]. European Journal of Pharmacology, 654(1), 117–121. doi:10.1016/j.ejphar.2010.11.022.CrossRefPubMed

Xu, Q., Yi, L. T., Pan, Y., Wang, X., Li, Y. C., Li, J. M., et al. (2008). Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents [Research Support, Non-U.S. Gov’t]. Progress in Neuropsychopharmacology and Biological Psychiatry, 32(3), 715–725. doi:10.1016/j.pnpbp.2007.11.020.CrossRef

Yang, X., Sheng, W., Ridgley, D. M., Haidekker, M. A., Sun, G. Y., & Lee, J. C. (2015). Astrocytes regulate alpha-secretase-cleaved soluble amyloid precursor protein secretion in neuronal cells: Involvement of group IIA secretory phospholipase A2. Neuroscience, 300, 508–517. doi:10.1016/j.neuroscience.2015.05.052.CrossRefPubMedPubMedCentral

Zhang, J., Barasch, N., Li, R. C., & Sapirstein, A. (2012). Inhibition of cytosolic phospholipase A(2) alpha protects against focal ischemic brain damage in mice [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Brain Research, 1471, 129–137. doi:10.1016/j.brainres.2012.06.031.CrossRefPubMed

Titel: Botanical Polyphenols Mitigate Microglial Activation and Microglia-Induced Neurotoxicity: Role of Cytosolic Phospholipase A2
verfasst von: Dennis Y. Chuang
Agnes Simonyi
Jiankun Cui
Dennis B. Lubahn
Zezong Gu
Grace Y. Sun
Publikationsdatum: 23.06.2016
Verlag: Springer US
Erschienen in: NeuroMolecular Medicine / Ausgabe 3/2016
Print ISSN: 1535-1084
Elektronische ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-016-8419-5

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Thrombektomie auch bei großen Infarkten von Vorteil

16.05.2024 Ischämischer Schlaganfall Nachrichten

Auch ein sehr ausgedehnter ischämischer Schlaganfall scheint an sich kein Grund zu sein, von einer mechanischen Thrombektomie abzusehen. Dafür spricht die LASTE-Studie, an der Patienten und Patientinnen mit einem ASPECTS von maximal 5 beteiligt waren.

Schwindelursache: Massagepistole lässt Otholiten tanzen

14.05.2024 Benigner Lagerungsschwindel Nachrichten

Wenn jüngere Menschen über ständig rezidivierenden Lagerungsschwindel klagen, könnte eine Massagepistole der Auslöser sein. In JAMA Otolaryngology warnt ein Team vor der Anwendung hochpotenter Geräte im Bereich des Nackens.

Schützt Olivenöl vor dem Tod durch Demenz?

10.05.2024 Morbus Alzheimer Nachrichten

Konsumieren Menschen täglich 7 Gramm Olivenöl, ist ihr Risiko, an einer Demenz zu sterben, um mehr als ein Viertel reduziert – und dies weitgehend unabhängig von ihrer sonstigen Ernährung. Dafür sprechen Auswertungen zweier großer US-Studien.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2016

Does Concurrent Use of Some Botanicals Interfere with Treatment of Tuberculosis?

Preserving Brain Function in Aging: The Anti-glycative Potential of Berry Fruit

Effects of Grape Skin Extract on Age-Related Mitochondrial Dysfunction, Memory and Life Span in C57BL/6J Mice

Clinacanthus nutans Protects Cortical Neurons Against Hypoxia-Induced Toxicity by Downregulating HDAC1/6

Phytochemicals in Ischemic Stroke