Browse > Article
http://dx.doi.org/10.4062/biomolther.2018.104

Anti-neuroinflammatory Effects of 12-Dehydrogingerdione in LPS-Activated Microglia through Inhibiting Akt/IKK/NF-κB Pathway and Activating Nrf-2/HO-1 Pathway  

Zhao, Dong (Natural Products Research Center, Korea Institute of Science and Technology)
Gu, Ming-Yao (Natural Products Research Center, Korea Institute of Science and Technology)
Xu, Jiu Liang (Natural Products Research Center, Korea Institute of Science and Technology)
Zhang, Li Jun (Natural Products Research Center, Korea Institute of Science and Technology)
Ryu, Shi Yong (Research Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology)
Yang, Hyun Ok (Natural Products Research Center, Korea Institute of Science and Technology)
Publication Information
Biomolecules & Therapeutics / v.27, no.1, 2019 , pp. 92-100 More about this Journal
Abstract
Ginger, one of worldwide consumed dietary spice, is not only famous as food supplements, but also believed to exert a variety of remarkable pharmacological activity as herbal remedies. In this study, a ginger constituent, 12-dehydrogingerdione (DHGD) was proven that has comparable anti-inflammatory activity with positive control 6-shogaol in inhibiting LPS-induced interleukin (IL)-6, tumor necrosis factor $(TNF)-{\alpha}$, prostaglandin (PG) $E_2$, nitric oxide (NO), inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, without interfering with COX-1 in cultured microglial cells. Subsequent mechanistic studies indicate that 12-DHGD may inhibit neuro-inflammation through suppressing the LPS-activated $Akt/IKK/NF-{\kappa}B$ pathway. Furthermore, 12-DHGD markedly promoted the activation of NF-E2-related factor (Nrf)-2 and heme oxygenase (HO)-1, and we demonstrated that the involvement of HO-1 on the production of pro-inflammatory mediators such as NO and $TNF-{\alpha}$ by using a HO-1 inhibitor, Zinc protoporphyrin (Znpp). These results indicate that 12-DHGD may protect against neuro-inflammation by inhibiting $Akt/IKK/I{\kappa}B/NF-{\kappa}B$ pathway and promoting Nrf-2/HO-1 pathway.
Keywords
Ginger; 12-Dehydrogingerdione; Neuro-inflammation; Microglial cells; Signaling pathway;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Wang, L., Chen, Y., Sternberg, P., Cai, J. (2008) Essential roles of the PI3K/Akt pathway in regulating Nrf2-dependent antioxidant functions in the RPE. Invest. Ophthalmol. Vis. Sci. 49, 1671-1678.   DOI
2 Young, H. Y., Luo, Y. L., Cheng, H. Y., Hsieh, W. C., Liao, J. C. and Peng, W. H. (2005) Analgesic and anti-inflammatory activities of [6]-gingerol. J. Ethnopharmacol. 96, 207-210.   DOI
3 Zandi, E., Rothwarf, D. M., Delhase, M., Hayakawa, M. and Karin, M. (1997) The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91, 243-252.   DOI
4 Zhao, D., Kwon, S. H., Chun, Y. S., Gu, M. Y. and Yang, H. O. (2017) Anti-neuroinflammatory effects of fucoxanthin via inhibition of Akt/NF-kappaB and MAPKs/AP-1 pathways and activation of PKA/CREB pathway in lipopolysaccharide-activated BV-2 microglial cells. Neurochem. Res. 42, 667-677.   DOI
5 Han, Y. A., Song, C. W., Koh, W. S., Yon, G. H., Kim, Y. S., Ryu, S. Y., Kwon, H. J. and Lee, K. H. (2013) Anti-inflammatory effects of the Zingiber officinale roscoe constituent 12-dehydrogingerdione in lipopolysaccharide-stimulated Raw 264.7 cells. Phytother. Res. 27, 1200-1205.   DOI
6 Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., Cooper, N. R., Eikelenboom, P., Emmerling, M., Fiebich, B. L., Finch, C. E., Frautschy, S., Griffin, W. S., Hampel, H., Hull, M., Landreth, G., Lue, L., Mrak, R., Mackenzie, I. R., McGeer, P. L., O'Banion, M. K., Pachter, J., Pasinetti, G., Plata-Salaman, C., Rogers, J., Rydel, R., Shen, Y., Streit, W., Strohmeyer, R., Tooyoma, I., Van Muiswinkel, F. L., Veerhuis, R., Walker, D., Webster, S., Wegrzyniak, B., Wenk, G. and Wyss-Coray, T. (2000) Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383-421.   DOI
7 Baeuerle, P. A. and Henkel, T. (1994) Function and activation of NF-kappa B in the immune system. Annu. Rev. Immunol. 12, 141-179.   DOI
8 Bai, D., Ueno, L. and Vogt, P. K. (2009) Akt-mediated regulation of NFkappaB and the essentialness of NFkappaB for the oncogenicity of PI3K and Akt. Int. J. Cancer 125, 2863-2870.   DOI
9 Gupta, S. C., Sundaram, C., Reuter, S. and Aggarwal, B. B. (2010) Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim. Biophys. Acta 1799, 775-787.   DOI
10 Ha, S. K., Moon, E., Ju, M. S., Kim, D. H., Ryu, J. H., Oh, M. S. and Kim, S. Y. (2012) 6-Shogaol, a ginger product, modulates neuroinflammation: a new approach to neuroprotection. Neuropharmacology 63, 211-223.   DOI
11 Infante-Duarte, C., Waiczies, S., Wuerfel, J. and Zipp, F. (2008) New developments in understanding and treating neuroinflammation. J. Mol. Med. 86, 975-985.   DOI
12 Jeong, Y. H., Park, J. S., Kim, D. H. and Kim, H. S. (2016) Lonchocarpine increases Nrf2/ARE-mediated antioxidant enzyme expression by modulating AMPK and MAPK signaling in brain astrocytes. Biomol. Ther. (Seoul) 24, 581-588.   DOI
13 Jung, J. S., Choi, M. J., Lee, Y. Y., Moon, B. I., Park, J. S., Kim, H. S. (2017) Suppression of Lipopolysaccharide-induced Neuroinflammation by Morin via MAPK, PI3K/Akt, and PKA/HO-1 Signaling Pathway Modulation. J. Agric. Food Chem. 65, 373-382.   DOI
14 Karin, M. and Delhase, M. (2000) The $I{\kappa}B$ kinase (IKK) and NF-${\kappa}B$: key elements of proinflammatory signalling. Semin. Immunol. 12, 85-98.   DOI
15 Koh, E. M., Kim, H. J., Kim, S., Choi, W. H., Choi, Y. H., Ryu, S. Y., Kim, Y. S., Koh, W. S. and Park, S. Y. (2009) Modulation of macrophage functions by compounds isolated from Zingiber officinale. Planta Med. 75, 148-151.   DOI
16 Syapin, P. J. (2008) Regulation of haeme oxygenase-1 for treatment of neuroinflammation and brain disorders. Br. J. Pharmacol. 155, 623-640.   DOI
17 Park, M., Bae, J. and Lee, D. S. (2008) Antibacterial activity of [10]-gingerol and [12]-gingerol isolated from ginger rhizome against periodontal bacteria. Phytother. Res. 22, 1446-1449.   DOI
18 Piirainen, S., Youssef, A., Song, C., Kalueff, A. V., Landreth, G. E., Malm, T. and Tian, L. (2017) Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer's disease: the emerging role for microglia? Neurosci. Biobehav. Rev. 77, 148-164.   DOI
19 Rahmani, A. H., Shabrmi, F. M. and Aly, S. M. (2014) Active ingredients of ginger as potential candidates in the prevention and treatment of diseases via modulation of biological activities. Int. J. Physiol. Pathophysiol. Pharmacol. 6, 125-136.
20 Sizemore, N., Leung, S. and Stark, G. R. (1999) Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol. Cell. Biol. 19, 4798-4805.   DOI
21 Tak, P. P. and Firestein, G. S. (2001) NF-kappaB: a key role in inflammatory diseases. J. Clin. Invest. 107, 7-11.   DOI
22 Tan, B. S., Kang, O., Mai, C. W., Tiong, K. H., Khoo, A. S., Pichika, M. R., Bradshaw, T. D. and Leong, C. O. (2013) 6-Shogaol inhibits breast and colon cancer cell proliferation through activation of peroxisomal proliferator activated receptor gamma (PPARgamma). Cancer Lett. 336, 127-139.   DOI
23 Teismann, P., Tieu, K., Cohen, O., Choi, D. K., Wu, D. C., Marks, D., Vila, M., Jackson-Lewis, V. and Przedborski, S. (2003) Pathogenic role of glial cells in Parkinson's disease. Mov. Disord. 18, 121-129.   DOI
24 Villarino, A. V., Kanno, Y. and O'Shea, J. J. (2017) Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol. 18, 374-384.   DOI
25 Mattson, M. P. and Meffert, M. K. (2006) Roles for NF-${\kappa}B$ in nerve cell survival, plasticity, and disease. Cell Death Differ. 13, 852-860.   DOI
26 Kwon, D. H., Cha, H. J., Choi, E. O., Leem, S. H., Kim, G. Y., Moon, S. K., Chang, Y. C., Yun, S. J., Hwang, H. J., Kim, B. W., Kim, W. J., Choi, Y. H. (2018) Schisandrin A suppresses lipopolysaccharide-indcued inflammation and oxidative stress in RAW 264.7 macrophages by suppressing the NF-B, MAPKs and PI3K/Akt pathways and activating Nrf2/HO-1 signaling. Int. J. Mol. Med. 41, 264-274.   DOI
27 Lee, H. Y., Park, S. H., Lee, M., Kim, H. J., Ryu, S. Y., Kim, N. D., Hwang, B. Y., Hong, J. T., Han, S. B. and Kim, Y. (2012) 1-Dehydro-[10]-gingerdione from ginger inhibits IKKbeta activity for NF-kappaB activation and suppresses NF-kappaB-regulated expression of inflammatory genes. Br. J. Pharmacol. 167, 128-140.   DOI
28 Li, F., Nitteranon, V., Tang, X., Liang, J., Zhang, G., Parkin, K. L. and Hu, Q. (2012) In vitro antioxidant and anti-inflammatory activities of 1-dehydro-[6]-gingerdione, 6-shogaol, 6-dehydroshogaol and hexahydrocurcumin. Food Chem. 135, 332-337.   DOI
29 Mercurio, F., Zhu, H., Murray, B. W., Shevchenko, A., Bennett, B. L., Li, J., Young, D. B., Barbosa, M., Mann, M., Manning, A. and Rao, A. (1997) IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science 278, 860-866.   DOI
30 Ozes, O. N., Mayo, L. D., Gustin, J. A., Pfeffer, S. R., Pfeffer, L. M. and Donner, D. B. (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401, 82-85.   DOI
31 Pan, M. H., Hsieh, M. C., Hsu, P. C., Ho, S. Y., Lai, C. S., Wu, H., Sang, S. and Ho, C. T. (2008) 6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages. Mol. Nutr. Food Res. 52, 1467-1477.   DOI
32 Dendorfer, U., Oettgen, P. and Libermann, T. A. (1994) Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide. Mol. Cell. Biol. 14, 4443-4454.   DOI
33 Choi, D. K., Koppula, S. and Suk, K. (2011) Inhibitors of microglial neurotoxicity: focus on natural products. Molecules 16, 1021-1043.   DOI
34 Cianciulli, A., Calvello, R., Porro, C., Trotta, T., Salvatore, R. and Panaro, M. A. (2016) PI3K/Akt signalling pathway plays a crucial role in the anti-inflammatory effects of curcumin in LPS-acivated microglia. Int. Immunopharmacol. 36, 282-290   DOI
35 Cuadrado, A., Martin-Moldes, Z., Ye, J. and Lastres-Becker, I. (2014) Transcription factors NRF2 and NF-kappaB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation. J. Biol. Chem. 289, 15244-15258.   DOI
36 Dugasani, S., Pichika, M. R., Nadarajah, V. D., Balijepalli, M. K., Tandra, S. and Korlakunta, J. N. (2010) Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J. Ethnopharmacol. 127, 515-520.   DOI
37 El-Ashmawy, N. E., Khedr, N. F., El-Bahrawy, H. A. and Abo Mansour, H. E. (2017) Ginger extract adjuvant to doxorubicin in mammary carcinoma: study of some molecular mechanisms. Eur. J. Nutr. 57, 981-989.
38 Giulian, D. and Baker, T. J. (1986) Characterization of ameboid microglia isolated from developing mammalian brain. J. Neurosci. 6, 2163-2178   DOI
39 Grzanna, R., Lindmark, L. and Frondoza, C. G. (2005) Ginger--an herbal medicinal product with broad anti-inflammatory actions. J. Med. Food 8, 125-132.   DOI
40 Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. and Gage, F. H. (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918-934.   DOI