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Oxidative Medicine and Cellular Longevity
Volume 2017, Article ID 5414297, 18 pages
https://doi.org/10.1155/2017/5414297
Research Article

Rhinacanthin C Alleviates Amyloid-β Fibrils’ Toxicity on Neurons and Attenuates Neuroinflammation Triggered by LPS, Amyloid-β, and Interferon-γ in Glial Cells

1Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, 321 Kuang Fu 2nd Road, Hsinchu 30011, Taiwan
2Institute of Molecular Medicine, College of Life Sciences, National Tsing Hua University, 101 Kuang Fu 2nd Road, Hsinchu 30013, Taiwan
3ARSOA Research & Development Center, AOB Keioh Group Corp., 2961 Kobuchisawa-cho, Hokuto, Yamanashi 408-8522, Japan

Correspondence should be addressed to Ming-Der Perng; wt.ude.uhtn.efil@gnrepdm and Shu-Fang Wen; wt.gro.irti@newgnafuhs

Received 21 May 2017; Revised 1 August 2017; Accepted 22 August 2017; Published 18 October 2017

Academic Editor: Amira Zarrouk

Copyright © 2017 Kai-An Chuang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. F. L. Heppner, R. M. Ransohoff, and B. Becher, “Immune attack: the role of inflammation in Alzheimer disease,” Nature Reviews Neuroscience, vol. 16, no. 6, pp. 358–372, 2015. View at Publisher · View at Google Scholar · View at Scopus
  2. R. R. Ji, Z. Z. Xu, and Y. J. Gao, “Emerging targets in neuroinflammation-driven chronic pain,” Nature Reviews Drug Discovery, vol. 13, no. 7, pp. 533–548, 2014. View at Publisher · View at Google Scholar · View at Scopus
  3. I. Morales, L. Guzmán-Martinez, C. Cerda-Troncoso, G. A. Farias, and R. B. Maccioni, “Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches,” Frontiers in Cellular Neuroscience, vol. 8, p. 112, 2014. View at Publisher · View at Google Scholar · View at Scopus
  4. M. Prinz and J. Priller, “Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease,” Nature Reviews Neuroscience, vol. 15, no. 5, pp. 300–312, 2014. View at Publisher · View at Google Scholar · View at Scopus
  5. S. Prokop, K. R. Miller, and F. L. Heppner, “Microglia actions in Alzheimer’s disease,” Acta Neuropathologica, vol. 126, no. 4, pp. 461–477, 2013. View at Publisher · View at Google Scholar · View at Scopus
  6. K. M. Lucin and T. Wyss-Coray, “Immune activation in brain aging and neurodegeneration: too much or too little?” Neuron, vol. 64, no. 1, pp. 110–122, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. R. G. Struble, T. Ala, P. R. Patrylo, G. J. Brewer, and X. X. Yan, “Is brain amyloid production a cause or a result of dementia of the Alzheimer’s type?” Journal of Alzheimer’s Disease, vol. 22, no. 2, pp. 393–399, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. P. D. Wes, F. A. Sayed, F. Bard, and L. Gan, “Targeting microglia for the treatment of Alzheimer’s disease,” Glia, vol. 64, no. 10, pp. 1710–1732, 2016. View at Publisher · View at Google Scholar · View at Scopus
  9. M. T. Heneka, M. J. Carson, J. El Khoury et al., “Neuroinflammation in Alzheimer’s disease,” The Lancet Neurology, vol. 14, no. 4, pp. 388–405, 2015. View at Publisher · View at Google Scholar · View at Scopus
  10. P. L. McGeer, J. Rogers, and E. G. McGeer, “Inflammation, antiinflammatory agents, and Alzheimer’s disease: the last 22 years,” Journal of Alzheimer’s Disease, vol. 54, no. 3, pp. 853–857, 2016. View at Publisher · View at Google Scholar · View at Scopus
  11. R. Baron, A. A. Babcock, A. Nemirovsky, B. Finsen, and A. Monsonego, “Accelerated microglial pathology is associated with Aβ in mouse models of Alzheimer’s disease,” Aging Cell, vol. 13, no. 4, pp. 584–595, 2014. View at Publisher · View at Google Scholar · View at Scopus
  12. A. M. Minoque, R. S. Jones, R. J. Kelly, C. L. McDonald, T. J. Connor, and M. A. Lynch, “Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice,” Neurobiology of Aging, vol. 35, no. 6, pp. 1442–1452, 2014. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Sastre, T. Klockgether, and M. T. Heneka, “Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms,” International Journal of Developmental Neuroscience, vol. 24, no. 2-3, pp. 167–176, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. A. Okello and P. Edison, “An early and late peak in microglial activation in Alzheimer’s disease trajectory,” Brain, vol. 140, no. 3, pp. 792–803, 2017. View at Publisher · View at Google Scholar
  15. M. L. Block, L. Zecca, and J. S. Hong, “Microglia-mediated neurotoxicity: uncovering the molecular mechanisms,” Nature Reviews Neuroscience, vol. 8, no. 1, pp. 57–69, 2007. View at Publisher · View at Google Scholar · View at Scopus
  16. P. Agostinho, R. A. Cunha, and C. Oliveira, “Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease,” Current Pharmaceutical Design, vol. 16, no. 25, pp. 2766–2778, 2010. View at Publisher · View at Google Scholar
  17. T. Wyss-Coray, “Inflammation in Alzheimer disease: driving force, bystander or beneficial response?” Nature Medicine, vol. 12, no. 9, pp. 1005–1015, 2006. View at Publisher · View at Google Scholar · View at Scopus
  18. J. T. Guo, J. Yu, D. Grass, F. C. de Beer, and M. S. Kindy, “Inflammation-dependent cerebral deposition of serum amyloid A protein in a mouse model of amyloidosis,” Journal of Neuroscience, vol. 22, no. 14, pp. 5900–5999, 2002. View at Google Scholar
  19. B. Liu and J. S. Hong, “Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention,” Journal of Pharmacology and Experimental Therapeutics, vol. 304, no. 1, pp. 1–7, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. G. C. Brown and J. J. Neher, “Microglial phagocytosis of live neurons,” Nature Reviews Neuroscience, vol. 15, no. 4, pp. 209–216, 2014. View at Publisher · View at Google Scholar · View at Scopus
  21. C. Cunningham, D. C. Wilcockson, S. Campion, K. Lunnon, and V. H. Perry, “Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration,” Journal of Neuroscience, vol. 25, no. 40, pp. 9275–9284, 2005. View at Publisher · View at Google Scholar · View at Scopus
  22. S. Gaikwad, S. Larionov, Y. Wang et al., “Signal regulatory protein-β1: a microglial modulator of phagocytosis in Alzheimer’s disease,” American Journal of Pathology, vol. 175, no. 6, pp. 2528–2539, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. J. El Khoury, S. Hickman, C. Thomas, L. Cao, S. Silverstein, and J. Loike, “Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils,” Nature, vol. 382, no. 6593, pp. 716–719, 1996. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Sendl, J. L. Chen, S. D. Jolad et al., “Two new naphthoquinones with antiviral activity from Rhinacanthus nasutus,” Journal of Natural Products, vol. 59, no. 8, pp. 808–811, 1996. View at Publisher · View at Google Scholar · View at Scopus
  25. N. Motohashi, “Nutraceuticals in Rhinacanthus nasutus (Hattaku-reishi-soh),” in Dietary Fiber, Fruit and Vegetable Consumption and Health, F. Klein and G. Möller, Eds., pp. 119–155, Nova Science Publishers, Inc., New York, NY, USA, 2010. View at Google Scholar
  26. T. S. Wu, H. C. Hsu, P. L. Wu et al., “Naphthoquinone esters from the root of Rhinacanthus nasutus,” Chemical and Pharmaceutical Bulletin, vol. 46, no. 3, pp. 413–418, 1998. View at Publisher · View at Google Scholar
  27. O. Kodama, H. Ichikawa, T. Akatsuka, V. Santisopasri, A. Kato, and Y. Hayashi, “Isolation and identification of an antifungal naphthopyran derivative from Rhinacanthus nasutus,” Journal of Natural Products, vol. 56, no. 2, pp. 292–294, 1993. View at Publisher · View at Google Scholar
  28. N. R. Farnsworth and N. Bunyapraphatsara, Thai Medicinal Plants: Recommended for Primary Health Care System, Mahidol University, Thailand, 1992.
  29. N. Siriwatanametanon, B. L. Fiebich, T. Efferth, J. M. Prieto, and M. Heinrich, “Traditionally used Thai medicinal plants: in vitro anti-inflammatory, anticancer and antioxidant activities,” Journal of Ethnopharmacology, vol. 130, no. 2, pp. 196–207, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. J. M. Brimson and T. Tencomnao, “Rhinacanthus nasutus protects cultured neuronal cells against hypoxia induced cell death,” Molecules, vol. 16, no. 8, pp. 6322–6338, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. J. M. Brimson, S. J. Brimson, C. A. Brimson, V. Rakkhitawatthana, and T. Tencomnao, “Rhinacanthus nasutus extracts prevent glutamate and amyloid-β neurotoxicity in HT-22 mouse hippocampal cells: possible active compounds include lupeol, stigmasterol and β-sitosterol,” International Journal of Molecular Sciences, vol. 13, no. 4, pp. 5074–5097, 2012. View at Publisher · View at Google Scholar · View at Scopus
  32. S. H. Adam, N. Giribabu, P. V. Rao et al., “Rhinacanthin C ameliorates hyperglycaemia, hyperlipidemia and pancreatic destruction in streptozotocin-nicotinamide induced adult male diabetic rats,” European Journal of Pharmacology, vol. 771, pp. 173–190, 2016. View at Publisher · View at Google Scholar · View at Scopus
  33. S. Tewtrakul, P. Tansakul, and P. Panichayupakaranant, “Effects of rhinacanthins from Rhinacanthus nasutus on nitric oxide, prostaglandin E2 and tumor necrosis factor-alpha releases using RAW264.7 macrophage cells,” Phytomedicine, vol. 16, no. 6-7, pp. 581–585, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. C. Z. Chang, S. C. Wu, A. L. Kwan, and C. L. Lin, “Rhinacanthin-C, a fat-soluble extract from Rhinacanthus nasutus, modulates high-mobility group box 1-related neuro-inflammation and subarachnoid hemorrhage-induced brain apoptosis in a rat model,” World Neurosurgery, vol. 86, pp. 349–360, 2016. View at Publisher · View at Google Scholar · View at Scopus
  35. M. Tomomura, R. Suzuki, Y. Shirataki, H. Sakagami, N. Tamura, and A. Tomomura, “Rhinacanthin C inhibits osteoclast differentiation and bone resorption: roles of TRAF6/TAK1/MAPKs/NF-κB/NFATc1 signaling,” PLoS One, vol. 10, no. 6, article e0130174, 2015. View at Publisher · View at Google Scholar · View at Scopus
  36. S. Tewtrakul, P. Tansakul, and P. Panichayupakaranant, “Anti-allergic principles of Rhinacanthus nasutus leaves,” Phytomedicine, vol. 16, no. 10, pp. 929–934, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. H. Horii, R. Suzuki, H. Sakagami, M. Tomomura, A. Tomomura, and Y. Shirataki, “New biological activities of Rhinacanthins from the root of Rhinacanthus nasutus,” Anticancer Research, vol. 33, no. 2, pp. 453–459, 2013. View at Google Scholar
  38. P. Sinha, S. Srivastava, N. Mishra, and N. P. Yadav, “New perspectives on antiacne plant drugs: contribution to modern therapeutics,” BioMed Research International, vol. 2014, Article ID 301304, 19 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  39. P. Puttarak, T. Charoonratana, and P. Panichayupakaranant, “Antimicrobial activity and stability of rhinacanthins-rich Rhinacanthus nasutus extract,” Phytomedicine, vol. 17, no. 5, pp. 323–327, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. S. Pethuan, P. Duangkaew, S. Sarapusit, E. Srisook, and P. Rongnoparut, “Inhibition against mosquito cytochrome P450 enzymes by rhinacanthin-A, -B, and -C elicits synergism on cypermethrin cytotoxicity in Spodoptera frugiperda cells,” Journal of Medical Entomology, vol. 49, no. 5, pp. 993–1000, 2012. View at Publisher · View at Google Scholar · View at Scopus
  41. G. M. Beaudoin 3rd, S. H. Lee, D. Singh et al., “Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex,” Nature Protocols, vol. 7, no. 9, pp. 1741–1754, 2012. View at Publisher · View at Google Scholar · View at Scopus
  42. G. Klaiman, T. L. Petzke, J. Hammond, and A. C. Leblanc, “Targets of caspase-6 activity in human neurons and Alzheimer disease,” Molecular and Cellular Proteomics, vol. 7, no. 8, pp. 1541–1555, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. U. K. Laemmli, “Cleavage of structural proteins during the assembly of the head of bacteriophage T4,” Nature, vol. 227, no. 5259, pp. 680–685, 1970. View at Publisher · View at Google Scholar · View at Scopus
  44. M. Noursadeghi, J. Tsang, T. Haustein, R. F. Miller, B. M. Chain, and D. R. Katz, “Quantitative imaging assay for NF-κB nuclear translocation in primary human macrophages,” Journal of Immunological Methods, vol. 329, no. 1-2, pp. 194–200, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. E. Meijering, M. Jacob, J. C. Sarria, P. Steiner, H. Hirling, and M. Unser, “Design and validation of a tool for neurite tracing and analysis in fluorescence microscopy images,” Cytometry, vol. 58, no. 2, pp. 167–176, 2004. View at Publisher · View at Google Scholar
  46. C. L. Masters and D. J. Selkoe, “Biochemistry of amyloid β-protein and amyloid deposits in Alzheimer disease,” Cold Spring Harbor Perspectives in Medicine, vol. 2, no. 6, article a006262, 2012. View at Publisher · View at Google Scholar · View at Scopus
  47. H. Y. Wu, E. Hudry, T. Hashimoto et al., “Amyloid β induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation,” Journal of Neuroscience, vol. 30, no. 7, pp. 2636–2649, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. J. C. Stroud, C. Liu, P. K. Teng, and D. Eisenberg, “Toxic fibrillary oligomers of amyloid-β have cross-β structure,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 20, pp. 7717–7722, 2012. View at Publisher · View at Google Scholar · View at Scopus
  49. K. Mosher and T. Wyss-Coray, “Microglial dysfunction in brain aging and Alzheimer’s disease,” Biochemical Pharmacology, vol. 88, no. 4, pp. 594–604, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. G. H. Doherty, “Nitric oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories,” Neuroscience Bulletin, vol. 27, no. 6, pp. 366–382, 2011. View at Publisher · View at Google Scholar · View at Scopus
  51. D. B. Kell and E. Pretorius, “On the translocation of bacteria and their lipopolysaccharides between blood and peripheral locations in chronic, inflammatory diseases: the central roles of LPS and LPS-induced cell death,” Integrative Biology, vol. 7, no. 11, pp. 1339–1377, 2015. View at Publisher · View at Google Scholar · View at Scopus
  52. L. J. Simmons, M. C. Suries-Zeigler, Y. Li, G. D. Ford, G. D. Newman, and B. D. Ford, “Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway,” Journal of Neuroinflammation, vol. 13, no. 1, p. 237, 2016. View at Publisher · View at Google Scholar · View at Scopus
  53. M. T. Heneka, D. T. Golenbock, and E. Latz, “Innate immunity in Alzheimer’s disease,” Nature Immunology, vol. 16, no. 3, pp. 229–236, 2015. View at Publisher · View at Google Scholar · View at Scopus
  54. M. N. Catorce and G. Gevorkian, “LPS-induced murine neuroinflammation model: main features and suitability for pre-clinical assessment of nutraceuticals,” Current Neuropharmacology, vol. 14, no. 2, pp. 155–164, 2016. View at Publisher · View at Google Scholar
  55. M. A. Burguillos, T. Deierborg, E. Kavanagh et al., “Caspase signalling controls microglia activation and neurotoxicity,” Nature, vol. 472, no. 7343, pp. 319–324, 2011. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Fricker, M. J. Oliva-Martin, and G. C. Brown, “Primary phagocytosis of viable neurons by microglia activated with LPS or Aβ is dependent on calreticulin/LRP phagocytic signaling,” Journal of Neuroinflammation, vol. 9, no. 196, 2012. View at Publisher · View at Google Scholar · View at Scopus
  57. J. G. Sheng, S. H. Bora, G. Xu, D. R. Borchelt, D. L. Price, and V. E. Koliatsos, “Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid β peptide in APPswe transgenic mice,” Neurobiology of Disease, vol. 14, no. 1, pp. 133–145, 2003. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Sy, M. Kitazawa, R. Medeiros et al., “Inflammation induced by infection potentiates pathological features in transgenic mice,” American Journal of Pathology, vol. 178, no. 6, pp. 2811–2822, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. J. Valero, G. Mastrella, I. Neiva, S. Sánchez, and J. O. Malva, “Long-term effects of an acute and systemic administration of LPS on adult neurogenesis and spatial memory,” Frontiers in Neuroscience, vol. 8, p. 83, 2014. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Lee, E. McGeer, and P. L. McGeer, “Activated human microglia stimulate neuroblastoma cells to upregulate production of beta amyloid protein and tau: implications for Alzheimer’s disease pathogenesis,” Neurobiology of Aging, vol. 36, no. 1, pp. 42–52, 2015. View at Publisher · View at Google Scholar · View at Scopus
  61. J. Miklossy, A. Kis, A. Radenovic et al., “Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes,” Neurobiology of Aging, vol. 27, no. 2, pp. 228–236, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. D. M. Norden, P. J. Trojanowski, E. Villanueva, E. Navarro, and J. P. Godbout, “Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge,” Glia, vol. 64, no. 2, pp. 300–316, 2016. View at Publisher · View at Google Scholar · View at Scopus
  63. M. G. Frank, S. A. Hershman, M. D. Weber, L. R. Watkins, and S. F. Maier, “Chronic exposure to exogenous glucocorticoids primes microglia to pro-inflammatory stimuli and induces NLRP3 mRNA in the hippocampus,” Psychoneuroendocrinology, vol. 40, pp. 191–200, 2014. View at Publisher · View at Google Scholar · View at Scopus
  64. A. Henn, S. Lund, M. Hedtjärn, A. Schrattenholz, P. Pörzgen, and M. Leist, “The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation,” ALTEX, vol. 26, no. 2, pp. 83–94, 2009. View at Publisher · View at Google Scholar
  65. B. Spittau, L. Wullkopf, X. Zhou, J. Rilka, D. Pfeifer, and K. Krieglstein, “Endogenous transforming growth factor-beta promotes quiescence of primary microglia in vitro,” Glia, vol. 61, no. 2, pp. 287–300, 2013. View at Publisher · View at Google Scholar · View at Scopus
  66. L. Qin, Y. Liu, J. S. Hong, and F. T. Crews, “NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration,” Glia, vol. 61, no. 6, pp. 855–868, 2013. View at Publisher · View at Google Scholar · View at Scopus
  67. C. K. Combs, J. C. Karlo, S. C. Kao, and G. E. Landreth, “β-Amyloid stimulation of microglia and monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis,” Journal of Neuroscience, vol. 21, no. 4, pp. 1179–1188, 2001. View at Google Scholar
  68. A. Klegeris, D. G. Walker, and P. L. McGeer, “Interaction of Alzheimer β-amyloid peptide with the human monocytic cell line THP-1 results in a protein kinase C-dependent secretion of tumor necrosis factor-α,” Brain Research, vol. 747, no. 1, pp. 114–121, 1997. View at Publisher · View at Google Scholar · View at Scopus
  69. G. Novarino, C. Fabrizi, R. Tonini et al., “Involvement of the intracellular ion channel CLIC1 in microglia-mediated β-amyloid-induced neurotoxicity,” Journal of Neuroscience, vol. 24, no. 23, pp. 5322–5330, 2004. View at Publisher · View at Google Scholar · View at Scopus
  70. M. Pascual-García, L. Rué, T. León et al., “Reciprocal negative cross-talk between liver X receptors (LXRs) and STAT1: effects on IFN-γ-induced inflammatory responses and LXR-dependent gene expression,” Journal of Immunology, vol. 190, no. 12, pp. 6520–6532, 2013. View at Publisher · View at Google Scholar · View at Scopus
  71. Y. Couch, L. Alvarez-Erviti, N. R. Sibson, M. J. Wood, and D. C. Anthony, “The acute inflammatory response to intranigral α-synuclein differs significantly from intranigral lipopolysaccharide and is exacerbated by peripheral inflammation,” Journal of Neuroinflammation, vol. 8, p. 166, 2011. View at Publisher · View at Google Scholar · View at Scopus
  72. J. G. McLamon, “Microglial chemotactic signaling factors in Alzheimer’s disease,” American Journal of Neurodegenerative Diseases, vol. 1, no. 3, pp. 199–204, 2012. View at Google Scholar
  73. J. Skuljec, H. Sun, R. Pul et al., “CCL5 induces a pro-inflammatory profile in microglia in vitro,” Cellular Immunology, vol. 270, no. 2, pp. 164–171, 2011. View at Publisher · View at Google Scholar · View at Scopus
  74. S. Camandola and M. P. Mattson, “NF-κB as a therapeutic target in neurodegenerative diseases,” Expert Opinion on Therapeutic Targets, vol. 11, no. 2, pp. 123–132, 2007. View at Publisher · View at Google Scholar · View at Scopus
  75. B. L. Fiebich, K. Lieb, S. Engels, and M. Heinrich, “Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells,” Journal of Neuroimmunology, vol. 132, no. 1-2, pp. 18–24, 2002. View at Publisher · View at Google Scholar · View at Scopus
  76. M. Srinivasan and D. K. Lahiri, “Significance of NF-κB as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer’s disease and multiple sclerosis,” Expert Opinion on Therapeutic Targets, vol. 19, no. 4, pp. 471–487, 2015. View at Publisher · View at Google Scholar · View at Scopus
  77. M. Leirós, E. Alonso, M. E. Rateb et al., “Gracilins: spongionella-derived promising compounds for Alzheimer disease,” Neuropharmacology, vol. 93, pp. 285–293, 2015. View at Publisher · View at Google Scholar · View at Scopus
  78. A. M. Floden, S. Li, and C. K. J. Combs, “β-Amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor α and NMDA receptors,” Neuroscience, vol. 25, no. 10, pp. 2566–2575, 2005. View at Publisher · View at Google Scholar · View at Scopus
  79. S. M. Shukla and S. K. Sharma, “Sinomenine inhibits microglial activation by Aβ and confers neuroprotection,” Journal of Neuroinflammation, vol. 8, p. 117, 2011. View at Publisher · View at Google Scholar · View at Scopus
  80. L. Meda, M. A. Cassatella, G. I. Szendrei et al., “Activation of microglial cells by β-amyloid protein and interferon-γ,” Nature, vol. 374, no. 6523, pp. 647–650, 1995. View at Publisher · View at Google Scholar
  81. A. A. Behensky, I. E. Yasny, A. M. Shuster, S. B. Seredenin, A. V. Petrov, and J. Cuevas, “Stimulation of sigma receptors with afobazole blocks activation of microglia and reduces toxicity caused by amyloid-β25–35,” Journal of Pharmacology and Experimental Therapeutics, vol. 347, no. 2, pp. 458–467, 2013. View at Publisher · View at Google Scholar · View at Scopus
  82. C. Lv, L. Wang, X. Liu et al., “Geniposide attenuates oligomeric Aβ(1-42)-induced inflammatory response by targeting RAGE-dependent signaling in BV2 cells,” Current Alzheimer Research, vol. 11, no. 5, pp. 430–440, 2014. View at Publisher · View at Google Scholar · View at Scopus
  83. S. E. Hickman, E. K. Allison, and J. El Khoury, “Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer’s disease mice,” Journal of Neuroscience, vol. 28, no. 33, pp. 8354–8360, 2008. View at Publisher · View at Google Scholar · View at Scopus
  84. F. Fang, L. F. Lue, S. Yan et al., “RAGE-dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease,” FASEB Journal, vol. 24, no. 4, pp. 1043–1055, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. C. Y. Lee and G. E. Landreth, “The role of microglia in amyloid clearance from the AD brain,” Journal of Neural Transmission, vol. 117, no. 8, pp. 949–960, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. T. Chaisit, P. Siripong, and S. Jianmongkol, “Rhinacanthin-C enhances doxorubicin cytotoxicity via inhibiting the functions of P-glycoprotein and MRP2 in breast cancer cells,” European Journal of Pharmacology, vol. 795, pp. 50–57, 2017. View at Publisher · View at Google Scholar
  87. Z. Fan, D. J. Brooks, A. Okello, and P. Edison, “An early and late peak in microglial activation in Alzheimer's disease trajectory,” Brain, vol. 140, no. 3, pp. 792–803, 2017. View at Publisher · View at Google Scholar