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

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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.

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Acknowledgments

This publication was made possible by NIH Grants 2P01 AG08357 from NIA and P50AT006273 from the National Center for Complementary and Alternative Medicines (NCCAM), the Office of Dietary Supplements (ODS), and the National Cancer Institute (NCI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIA, NCCAM, ODS, NCI, or the National Institutes of Health.

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Authors and Affiliations

  1. Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, USA

    Dennis Y. Chuang, Jiankun Cui, Zezong Gu & Grace Y. Sun

  2. Center for Translational Neuroscience, University of Missouri, Columbia, MO, USA

    Dennis Y. Chuang, Agnes Simonyi, Jiankun Cui, Dennis B. Lubahn, Zezong Gu & Grace Y. Sun

  3. Center for Botanical Interaction Studies, University of Missouri, Columbia, MO, USA

    Dennis Y. Chuang, Agnes Simonyi, Dennis B. Lubahn, Zezong Gu & Grace Y. Sun

  4. Department of Biochemistry, University of Missouri, 117 Schweitzer Hall, Columbia, MO, 65211, USA

    Agnes Simonyi, Dennis B. Lubahn & Grace Y. Sun

  5. Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO, USA

    Jiankun Cui & Zezong Gu

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  1. Dennis Y. Chuang
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Correspondence to Grace Y. Sun.

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Chuang, D.Y., Simonyi, A., Cui, J. et al. Botanical Polyphenols Mitigate Microglial Activation and Microglia-Induced Neurotoxicity: Role of Cytosolic Phospholipase A2 . Neuromol Med 18, 415–425 (2016). https://doi.org/10.1007/s12017-016-8419-5

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