Anti-Inflammatory and Anti-Migratory Activities of Isoquinoline-1-Carboxamide Derivatives in LPS-Treated BV2 Microglial Cells via Inhibition of MAPKs/NF-κB Pathway
Abstract
:1. Introduction
2. Results
2.1. Effects of Isoquinoline-1-carboxamides on Viabilities of BV2 Cells
2.2. Effects of Isoquinoline-1-carboxamides on the Production of Pro- and Anti-Inflammatory Mediators in LPS-Treated BV2 Cells
2.3. Effect of HSR1101 on LPS-Stimulated iNOS and COX-2 Expression in BV2 Cells
2.4. Effects of HSR1101 on LPS-Induced NF-κB Translocation and IκBα Phosphorylation in BV2 Cells
2.5. Effect of HSR1101 on LPS-Induced Cell Migration in BV2 Cells
2.6. Effect of HSR1101 on MAPK Phosphorylation in LPS-Treated BV2 Cells
2.7. Effects of MAPK Inhibitors on LPS-Induced Pro-Inflammatory Mediators and Cell Migration in BV2 Cells
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. Synthesis of Isoquinoline-1-carboxamide Derivatives
4.3. Cell Culture, Treatments, and Measurements of Cell Viability
4.4. Measurements of IL-6, TNF-α, NO, and IL-10
4.5. Western Blotting
4.6. Immunocytochemistry
4.7. Cell Migration Assays
4.7.1. Wound Healing Assay
4.7.2. Transwell Migration Assay
4.8. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
CNS | Central nervous system |
COX-2 | Cyclooxygenase-2 |
ERK1/2 | Extracellular signal-regulated kinase 1/2 |
IκBs | Inhibitors of kappa B |
IL | Interleukin |
iNOS | Inducible nitric oxide synthase |
JNK | C-Jun N-terminal kinase |
LPS | Lipopolysaccharide |
MAPK | Mitogen-activated protein kinase |
NF-κB | Nuclear factor-kappa B |
NO | Nitric oxide |
PD | Parkinson’s disease |
TLR | Toll-like receptor |
TNF-α | Tumor necrosis factor-alpha |
References
- Amor, S.; Puentes, F.; Baker, D.; Van Der Valk, P. Inflammation in neurodegenerative diseases. Immunology 2010, 129, 154–169. [Google Scholar] [CrossRef] [PubMed]
- Block, M.L.; Zecca, L.; Hong, J.S. Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nat. Rev. Neurosci. 2007, 8, 57–69. [Google Scholar] [CrossRef] [PubMed]
- Barron, K.D. The microglial cell. A historical review. J. Neurol. Sci. 1995, 134, 57–68. [Google Scholar] [CrossRef]
- Nakajima, K.; Kohsaka, S. Functional roles of microglia in the central nervous system. Hum. Cell 1998, 11, 141–155. [Google Scholar]
- Neumann, H.; Kotter, M.R.; Franklin, R.J. Debris clearance by microglia: An essential link between degeneration and regeneration. Brain 2009, 132, 288–295. [Google Scholar] [CrossRef]
- Zhang, Q.; Lu, Y.; Bian, H.; Guo, L.; Zhu, H. Activation of the α7 nicotinic receptor promotes lipopolysaccharide-induced conversion of M1 microglia to M2. Am. J. Transl. Res. 2017, 9, 971. [Google Scholar]
- Glass, C.K.; Saijo, K.; Winner, B.; Marchetto, M.C.; Gage, F.H. Mechanisms underlying inflammation in neurodegeneration. Cell 2010, 140, 918–934. [Google Scholar] [CrossRef] [Green Version]
- Liu, B.; Hong, J.-S. Role of microglia in inflammation-mediated neurodegenerative diseases: Mechanisms and strategies for therapeutic intervention. J. Pharmacol. Exp. Ther. 2003, 304, 1–7. [Google Scholar] [CrossRef] [Green Version]
- Moniruzzaman, M.; Bose, S.; Kim, Y.M.; Chin, Y.W.; Cho, J. The ethyl acetate fraction from Physalis alkekengi inhibits LPS-induced pro-inflammatory mediators in BV2 cells and inflammatory pain in mice. J. Ethnopharmacol. 2016, 181, 26–36. [Google Scholar] [CrossRef]
- Moniruzzaman, M.; Lee, G.; Bose, S.; Choi, M.; Jung, J.K.; Lee, H.; Cho, J. Antioxidant and Anti-inflammatory Activities of N-((3,4-Dihydro-2H-benzo[h]chromene-2-yl)methyl)-4-methoxyaniline in LPS-Induced BV2 Microglial Cells. Biol. Pharm. Bull. 2015, 38, 1831–1835. [Google Scholar] [CrossRef] [Green Version]
- Dou, Y.; Wu, H.J.; Li, H.Q.; Qin, S.; Wang, Y.E.; Li, J.; Lou, H.F.; Chen, Z.; Li, X.M.; Luo, Q.M.; et al. Microglial migration mediated by ATP-induced ATP release from lysosomes. Cell Res. 2012, 22, 1022–1033. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nimmerjahn, A.; Kirchhoff, F.; Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308, 1314–1318. [Google Scholar] [CrossRef] [Green Version]
- Lykhmus, O.; Mishra, N.; Koval, L.; Kalashnyk, O.; Gergalova, G.; Uspenska, K.; Komisarenko, S.; Soreq, H.; Skok, M. Molecular mechanisms regulating LPS-induced inflammation in the brain. Front. Mol. Neurosci. 2016, 9, 19. [Google Scholar] [CrossRef] [Green Version]
- Gao, H.M.; Jiang, J.; Wilson, B.; Zhang, W.; Hong, J.S.; Liu, B. Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: Relevance to Parkinson’s disease. J. Neurochem. 2002, 81, 1285–1297. [Google Scholar] [CrossRef] [PubMed]
- Gibbons, H.M.; Dragunow, M. Microglia induce neural cell death via a proximity-dependent mechanism involving nitric oxide. Brain Res. 2006, 1084, 1–15. [Google Scholar] [CrossRef]
- Ling, Z.; Zhu, Y.; Tong, C.; Snyder, J.A.; Lipton, J.W.; Carvey, P.M. Progressive dopamine neuron loss following supra-nigral lipopolysaccharide (LPS) infusion into rats exposed to LPS prenatally. Exp. Neurol. 2006, 199, 499–512. [Google Scholar] [CrossRef] [PubMed]
- Peng, S.; Jia, J.; Sun, J.; Xie, Q.; Zhang, X.; Deng, Y.; Yi, L. LXW7 attenuates inflammation via suppressing Akt/nuclear factor kappa B and mitogen-activated protein kinases signaling pathways in lipopolysaccharide-stimulated BV2 microglial cells. Int. Immunopharmacol. 2019, 77, 105963. [Google Scholar] [CrossRef]
- Subedi, L.; Lee, J.H.; Yumnam, S.; Ji, E.; Kim, S.Y. Anti-Inflammatory Effect of Sulforaphane on LPS-Activated Microglia Potentially through JNK/AP-1/NF-kappaB Inhibition and Nrf2/HO-1 Activation. Cells 2019, 8, 194. [Google Scholar] [CrossRef] [Green Version]
- Tak, P.P.; Firestein, G.S. NF-κB: A key role in inflammatory diseases. J. Clin. Invest. 2001, 107, 7–11. [Google Scholar] [CrossRef]
- Bui, B.P.; Oh, Y.; Lee, H.; Cho, J. Inhibition of inflammatory mediators and cell migration by 1,2,3,4-tetrahydroquinoline derivatives in LPS-stimulated BV2 microglial cells via suppression of NF-kappaB and JNK pathway. Int. Immunopharmacol. 2020, 80, 106231. [Google Scholar] [CrossRef]
- Pocivavsek, A.; Burns, M.P.; Rebeck, G.W. Low-density lipoprotein receptors regulate microglial inflammation through c-Jun N-terminal kinase. Glia 2009, 57, 444–453. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kim, B.W.; Koppula, S.; Hong, S.S.; Jeon, S.B.; Kwon, J.H.; Hwang, B.Y.; Park, E.J.; Choi, D.K. Regulation of microglia activity by glaucocalyxin-A: Attenuation of lipopolysaccharide-stimulated neuroinflammation through NF-kappaB and p38 MAPK signaling pathways. PLoS ONE 2013, 8, e55792. [Google Scholar] [CrossRef] [PubMed]
- Deng, Z.; Sui, G.; Rosa, P.M.; Zhao, W. Radiation-induced c-Jun activation depends on MEK1-ERK1/2 signaling pathway in microglial cells. PLoS ONE 2012, 7, e36739. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhu, C.; Xiong, Z.; Chen, X.; Peng, F.; Hu, X.; Chen, Y.; Wang, Q. Artemisinin attenuates lipopolysaccharide-stimulated proinflammatory responses by inhibiting NF-κB pathway in microglia cells. PLoS ONE 2012, 7, e35125. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nam, H.Y.; Nam, J.H.; Yoon, G.; Lee, J.-Y.; Nam, Y.; Kang, H.-J.; Cho, H.-J.; Kim, J.; Hoe, H.-S. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice. J. Neuroinflammation 2018, 15, 271. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hu, H.; Li, Z.; Zhu, X.; Lin, R.; Chen, L. Salidroside reduces cell mobility via NF-κB and MAPK signaling in LPS-induced BV2 microglial cells. Evid. Based Complementary Altern. Med. 2014, 2014. [Google Scholar] [CrossRef]
- Cai, B.; Seong, K.-J.; Bae, S.-W.; Chun, C.; Kim, W.-J.; Jung, J.-Y. A synthetic diosgenin primary amine derivative attenuates LPS-stimulated inflammation via inhibition of NF-κB and JNK MAPK signaling in microglial BV2 cells. Int. Immunopharmacol. 2018, 61, 204–214. [Google Scholar] [CrossRef]
- Choi, Y.; Moon, A.; Kim, Y.C. A pinusolide derivative, 15-methoxypinusolidic acid from Biota orientalis inhibits inducible nitric oxide synthase in microglial cells: Implication for a potential anti-inflammatory effect. Int. Immunopharmacol. 2008, 8, 548–555. [Google Scholar] [CrossRef]
- Gee, M.S.; Kim, S.W.; Kim, N.; Lee, S.J.; Oh, M.S.; Jin, H.K.; Bae, J.S.; Inn, K.S.; Kim, N.J.; Lee, J.K. A Novel and Selective p38 Mitogen-Activated Protein Kinase Inhibitor Attenuates LPS-Induced Neuroinflammation in BV2 Microglia and a Mouse Model. Neurochem. Res. 2018, 43, 2362–2371. [Google Scholar] [CrossRef]
- Jeong, Y.H.; Kim, Y.; Song, H.; Chung, Y.S.; Park, S.B.; Kim, H.S. Anti-inflammatory effects of alpha-galactosylceramide analogs in activated microglia: Involvement of the p38 MAPK signaling pathway. PLoS ONE 2014, 9, e87030. [Google Scholar] [CrossRef] [Green Version]
- Anttila, J.E.; Whitaker, K.W.; Wires, E.S.; Harvey, B.K.; Airavaara, M. Role of microglia in ischemic focal stroke and recovery: Focus on Toll-like receptors. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2017, 79, 3–14. [Google Scholar] [CrossRef]
- Li, N.; Liu, B.W.; Ren, W.Z.; Liu, J.X.; Li, S.N.; Fu, S.P.; Zeng, Y.L.; Xu, S.Y.; Yan, X.; Gao, Y.J.; et al. GLP-2 Attenuates LPS-Induced Inflammation in BV-2 Cells by Inhibiting ERK1/2, JNK1/2 and NF-kappaB Signaling Pathways. Int. J. Mol. Sci. 2016, 17, 190. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, R.P.; Zou, M.; Wang, J.Y.; Zhu, J.J.; Lai, J.M.; Zhou, L.L.; Chen, S.F.; Zhang, X.; Zhu, J.H. Paroxetine ameliorates lipopolysaccharide-induced microglia activation via differential regulation of MAPK signaling. J. Neuroinflammation 2014, 11, 47. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mogi, M.; Harada, M.; Riederer, P.; Narabayashi, H.; Fujita, K.; Nagatsu, T. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci. Lett. 1994, 165, 208–210. [Google Scholar] [CrossRef]
- Sriram, K.; Matheson, J.M.; Benkovic, S.A.; Miller, D.B.; Luster, M.I.; O’Callaghan, J.P. Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: Role of TNF-alpha. FASEB J. 2006, 20, 670–682. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Campbell, I.L.; Abraham, C.R.; Masliah, E.; Kemper, P.; Inglis, J.D.; Oldstone, M.B.; Mucke, L. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc. Natl. Acad. Sci. USA 1993, 90, 10061–10065. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bruhwyler, J.; Chleide, E.; Liégeois, J.-F.; Carreer, F. Nitric oxide: A new messenger in the brain. Neurosci. Biobehav. Rev. 1993, 17, 373–384. [Google Scholar] [CrossRef]
- Nathan, C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992, 6, 3051–3064. [Google Scholar] [CrossRef]
- Park, J.-S.; Woo, M.-S.; Kim, D.-H.; Hyun, J.-W.; Kim, W.-K.; Lee, J.-C.; Kim, H.-S. Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells. J. Pharmacol. Exp. Ther. 2007, 320, 1237–1245. [Google Scholar] [CrossRef] [Green Version]
- Zhu, J.; Jiang, L.; Liu, Y.; Qian, W.; Liu, J.; Zhou, J.; Gao, R.; Xiao, H.; Wang, J. MAPK and NF-kappaB pathways are involved in bisphenol A-induced TNF-alpha and IL-6 production in BV2 microglial cells. Inflammation 2015, 38, 637–648. [Google Scholar] [CrossRef]
- Lobo-Silva, D.; Carriche, G.M.; Castro, A.G.; Roque, S.; Saraiva, M. Balancing the immune response in the brain: IL-10 and its regulation. J. Neuroinflammation 2016, 13, 297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Magalhaes, C.A.; Carvalho, M.D.G.; Sousa, L.P.; Caramelli, P.; Gomes, K.B. Alzheimer’s disease and cytokine IL-10 gene polymorphisms: Is there an association? Arq. Neuropsiquiatr. 2017, 75, 649–656. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Murphy, S. Production of nitric oxide by glial cells: Regulation and potential roles in the CNS. Glia 2000, 29, 1–13. [Google Scholar] [CrossRef]
- Dawson, T.M.; Dawson, V.L. Nitric oxide signaling in neurodegeneration and cell death. In Advances in Pharmacology; Elsevier: Amsterdam, The Netherlands, 2018; Volume 82, pp. 57–83. [Google Scholar]
- Dubois, R.N.; Abramson, S.B.; Crofford, L.; Gupta, R.A.; Simon, L.S.; Van De Putte, L.B.; Lipsky, P.E. Cyclooxygenase in biology and disease. Faseb J. 1998, 12, 1063–1073. [Google Scholar] [CrossRef] [Green Version]
- Wyss-Coray, T.; Rogers, J. Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harb. Perspect. Med. 2012, 2, a006346. [Google Scholar] [CrossRef]
- Liang, X.; Wu, L.; Wang, Q.; Hand, T.; Bilak, M.; McCullough, L.; Andreasson, K. Function of COX-2 and prostaglandins in neurological disease. J. Mol. Neurosci. 2007, 33, 94–99. [Google Scholar] [CrossRef]
- Hoesel, B.; Schmid, J.A. The complexity of NF-κB signaling in inflammation and cancer. Mol. Cancer 2013, 12, 86. [Google Scholar] [CrossRef] [Green Version]
- Scheiblich, H.; Roloff, F.; Singh, V.; Stangel, M.; Stern, M.; Bicker, G. Nitric oxide/cyclic GMP signaling regulates motility of a microglial cell line and primary microglia in vitro. Brain Res. 2014, 1564, 9–21. [Google Scholar] [CrossRef]
- Chen, A.; Kumar, S.M.; Sahley, C.L.; Muller, K.J. Nitric oxide influences injury-induced microglial migration and accumulation in the leech CNS. J. Neurosci. Off. J. Soc. Neurosci. 2000, 20, 1036–1043. [Google Scholar] [CrossRef] [Green Version]
- Bohush, A.; Niewiadomska, G.; Filipek, A. Role of mitogen activated protein kinase signaling in parkinson’s disease. Int. J. Mol. Sci. 2018, 19, 2973. [Google Scholar] [CrossRef] [Green Version]
- Crews, L.; Masliah, E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum. Mol. Genet. 2010, 19, R12–R20. [Google Scholar] [CrossRef] [PubMed]
- Sun, J.; Nan, G. The extracellular signal-regulated kinase 1/2 pathway in neurological diseases: A potential therapeutic target. Int. J. Mol. Med. 2017, 39, 1338–1346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hsu, M.-Y.; Yang, C.-Y.; Hsu, W.-H.; Lin, K.-H.; Wang, C.-Y.; Shen, Y.-C.; Chen, Y.-C.; Chau, S.-F.; Tsai, H.-Y.; Cheng, C.-M. Monitoring the VEGF level in aqueous humor of patients with ophthalmologically relevant diseases via ultrahigh sensitive paper-based ELISA. Biomaterials 2014, 35, 3729–3735. [Google Scholar] [CrossRef]
- Olson, J.K.; Miller, S.D. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J. Immunol. 2004, 173, 3916–3924. [Google Scholar] [CrossRef] [Green Version]
- Carty, M.; Bowie, A.G. Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem. Pharmacol. 2011, 81, 825–837. [Google Scholar] [CrossRef]
- Luo, Q.; Yan, X.; Bobrovskaya, L.; Ji, M.; Yuan, H.; Lou, H.; Fan, P. Anti-neuroinflammatory effects of grossamide from hemp seed via suppression of TLR-4-mediated NF-kappaB signaling pathways in lipopolysaccharide-stimulated BV2 microglia cells. Mol. Cell Biochem. 2017, 428, 129–137. [Google Scholar] [CrossRef]
- Lee, K.; Park, C.; Oh, Y.; Lee, H.; Cho, J. Antioxidant and neuroprotective effects of N-((3, 4-dihydro-2H-benzo [h] chromen-2-yl) methyl)-4-methoxyaniline in primary cultured rat cortical cells: Involvement of ERK-CREB signaling. Molecules 2018, 23, 669. [Google Scholar] [CrossRef] [Green Version]
- Hu, H.; Li, Z.; Zhu, X.; Lin, R.; Peng, J.; Tao, J.; Chen, L. GuaLou GuiZhi decoction inhibits LPS-induced microglial cell motility through the MAPK signaling pathway. Int. J. Mol. Med. 2013, 32, 1281–1286. [Google Scholar] [CrossRef] [Green Version]
- Bose, S.; Kim, S.; Oh, Y.; Moniruzzaman, M.; Lee, G.; Cho, J. Effect of CCL2 on BV2 microglial cell migration: Involvement of probable signaling pathways. Cytokine 2016, 81, 39–49. [Google Scholar] [CrossRef]
Pro-Inflammatory Mediators | IC50 Value a | ||||
---|---|---|---|---|---|
HSR1101 | HSR1102 | HSR1103 | HSR1105 | HSR1106 | |
IL-6 | 39.13 | 29.52 | 30.55 | 56.59 | 76.38 |
TNF-α | 29.18 | 25.92 | 70.17 | 71.66 | 67.81 |
NO | 22.84 | 28.52 | 22.42 | 42.27 | 75.13 |
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Do, H.T.T.; Bui, B.P.; Sim, S.; Jung, J.-K.; Lee, H.; Cho, J. Anti-Inflammatory and Anti-Migratory Activities of Isoquinoline-1-Carboxamide Derivatives in LPS-Treated BV2 Microglial Cells via Inhibition of MAPKs/NF-κB Pathway. Int. J. Mol. Sci. 2020, 21, 2319. https://doi.org/10.3390/ijms21072319
Do HTT, Bui BP, Sim S, Jung J-K, Lee H, Cho J. Anti-Inflammatory and Anti-Migratory Activities of Isoquinoline-1-Carboxamide Derivatives in LPS-Treated BV2 Microglial Cells via Inhibition of MAPKs/NF-κB Pathway. International Journal of Molecular Sciences. 2020; 21(7):2319. https://doi.org/10.3390/ijms21072319
Chicago/Turabian StyleDo, Ha Thi Thu, Bich Phuong Bui, Seongrak Sim, Jae-Kyung Jung, Heesoon Lee, and Jungsook Cho. 2020. "Anti-Inflammatory and Anti-Migratory Activities of Isoquinoline-1-Carboxamide Derivatives in LPS-Treated BV2 Microglial Cells via Inhibition of MAPKs/NF-κB Pathway" International Journal of Molecular Sciences 21, no. 7: 2319. https://doi.org/10.3390/ijms21072319