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Gallic Acid Attenuated LPS-Induced Neuroinflammation: Protein Aggregation and Necroptosis

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Abstract

Gallic acid (3,4,5-trihydroxybenzoic acid, GA), a phenolic acid, is ubiquitous in almost all parts of the plant. In the present study, a neuroinflammatory rat model using intranigral infusion of lipopolysaccharides (LPS, 4 μg/μL) was employed to study the neuroprotective effect of GA which was orally administered daily. Compared with the vehicle-treated rats, systemic administration of GA (100 mg/kg) significantly attenuated LPS-induced increases in glial fibrillary acidic protein (a biomarker of activated astrocytes) and ED-1 (a biomarker of activated microglia), as well as inducible nitric oxide synthase (iNOS, a proinflammatory enzyme) and interleukin-1β (a proinflammatory cytokine), in the LPS-infused substantia nigra (SN) of rat brain. At the same time, GA attenuated LPS-induced elevation in heme oxygenase-1 level (a redox-regulated protein) and α-synuclein aggregation (a hallmark of CNS neurodegeneration), suggesting that GA is capable of inhibiting LPS-induced oxidative stress and protein conjugation. Furthermore, GA prevented LPS-induced caspase 3 activation (a biomarker of programmed cell death) and LPS-induced increases in receptor-interacting protein kinase (RIPK)-1 and RIPK-3 levels (biomarkers of necroptosis), indicating that GA inhibited LPS-induced apoptosis and necroptosis in the nigrostriatal dopaminergic system of rat brain. Moreover, an in vitro study was employed to investigate the anti-inflammatory effect of GA on BV2 microglial cells which were subjected to LPS (1 μg/mL) treatment. Consistently, co-incubation of GA diminished LPS-induced increases in iNOS mRNA and iNOS protein expression in the treated BV-2 cells as well as NO production in the culture medium. The anti-oxidative activity of GA was evaluated using iron-induced lipid peroxidation of brain homogenates. After 3-h incubation at 37 °C, GA was more potent than glutathione and less potent than trolox in inhibiting iron-induced lipid peroxidation. Conclusively, the present study suggests that GA is anti-inflammatory via attenuating LPS-induced neuroinflammation, oxidative stress, and protein conjugation. Furthermore, GA prevented LPS-induced programmed cell deaths of nigrostriatal dopaminergic neurons of the rat brain, suggesting that GA may be neuroprotective by attenuating neuroinflammation in CNS neurodegenerative diseases.

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Acknowledgments

The authors express their gratitude to Dr. C.Y. Chai at the Institute of Biomedical Sciences, Academia Sinica, for his encouragement and support. Special thanks are due to Dr. R.K. Freund at the Department of Pharmacology, University of Colorado, Anschutz, CO, USA, for editing this paper.

Funding

This study was supported by MOST107-2320-B-010-019-MY3 and 107DN08, Taipei, Taiwan, R.O.C.

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Author notes

  1. Yu-Ling Liu and Chia-Chi Hsu contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan

    Yu-Ling Liu & Anya Maan-Yuh Lin

  2. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

    Chia-Chi Hsu

  3. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

    Hui-Ju Huang & Anya Maan-Yuh Lin

  4. Faculty of Pharmacy, National Yang-Ming University, Taipei, Taiwan

    Chih-Jung Chang & Anya Maan-Yuh Lin

  5. Department of Pharmacy, Far Eastern Memorial Hospital, Banciao, New Taipei City, 220, Taiwan

    Shu-Hui Sun

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Correspondence to Shu-Hui Sun or Anya Maan-Yuh Lin.

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The use of animals has been approved by the Institutional Animal Care and Use Committee of Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.. The approval number is IACUC2018. All experiments were performed in the accordance with relevant guidelines and regulation.

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Effects of GA on LPS-induced HO-1 in BV-2 cells. (A) BV-2 cells were incubated with LPS (1 μg/mL) plus GA (25-50 μM) for 24 h. Western blot assay was employed for measuring HO-1 expression. Graphs show statistical results from HO-1 protein expression. Values are the mean ± S.E.M. (n = 3/group). *, p < 0.05 in the LPS-treated BV-2 cells compared with vehicle-treated BV-2 cells; #, p < 0.05 in the LPS plus GA-treated BV-2 cells compared with LPS-treated BV-2 cells by t-test. (PNG 199 kb)

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Liu, YL., Hsu, CC., Huang, HJ. et al. Gallic Acid Attenuated LPS-Induced Neuroinflammation: Protein Aggregation and Necroptosis. Mol Neurobiol 57, 96–104 (2020). https://doi.org/10.1007/s12035-019-01759-7

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  • DOI: https://doi.org/10.1007/s12035-019-01759-7

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