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Korean Red Ginseng and Ginsenoside-Rb1/-Rg1 Alleviate Experimental Autoimmune Encephalomyelitis by Suppressing Th1 and Th17 Cells and Upregulating Regulatory T Cells

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Abstract

The effects of Korean red ginseng extract (KRGE) on autoimmune disorders of the nervous system are not clear. We investigated whether KRGE has a beneficial effect on acute and chronic experimental autoimmune encephalomyelitis (EAE). Pretreatment (daily from 10 days before immunization with myelin basic protein peptide) with KRGE significantly attenuated clinical signs and loss of body weight and was associated with the suppression of spinal demyelination and glial activation in acute EAE rats, while onset treatment (daily after the appearance of clinical symptoms) did not. The suppressive effect of KRGE corresponded to the messenger RNA (mRNA) expression of proinflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin [IL]-1β), chemokines (RANTES, monocyte chemotactic protein-1 [MCP-1], and macrophage inflammatory protein-1α [MIP-1α]), adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], and platelet endothelial cell adhesion molecule [PECAM-1]), and inducible nitric oxide synthase in the spinal cord after immunization. Interestingly, in acute EAE rats, pretreatment with KRGE significantly reduced the population of CD4+, CD4+/IFN-γ+, and CD4+/IL-17+ T cells in the spinal cord and lymph nodes, corresponding to the downregulation of mRNA expression of IFN-γ, IL-17, and IL-23 in the spinal cord. On the other hand, KRGE pretreatment increased the population of CD4+/Foxp3+ T cells in the spinal cord and lymph nodes of these rats, corresponding to the upregulation of mRNA expression of Foxp3 in the spinal cord. Interestingly, intrathecal pretreatment of rats with ginsenosides (Rg1 and Rb1) significantly decreased behavioral impairment. These results strongly indicate that KRGE has a beneficial effect on the development and progression of EAE by suppressing T helper 1 (Th1) and Th17 T cells and upregulating regulatory T cells. Additionally, pre- and onset treatment with KRGE alleviated neurological impairment of myelin oligodendrocyte glycoprotein35–55-induced mouse model of chronic EAE. These results warrant further investigation of KRGE as preventive or therapeutic strategies for autoimmune disorders, such as multiple sclerosis.

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Abbreviations

APG:

Acidic polysaccharide of Panax ginseng

BBB:

Blood–brain barrier

CNS:

Central nervous system

EAE:

Experimental autoimmune encephalomyelitis

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

HRP:

Horseradish peroxidase

Iba-1:

Anti-ionized calcium binding adaptor molecule-1

ICAM-1:

Intercellular adhesion molecule-1

IFN-β:

Interferon beta

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

KRGE:

Korean red ginseng extract

MBP:

Myelin basic protein

MS:

Multiple sclerosis

MCP-1:

Monocyte chemotactic protein-1

MIP-1α:

Macrophage inflammatory protein-1α

PDGFαR:

Platelet-derived growth factor

PTX:

Pertussis toxin

TCR:

T cell receptor

Th1:

T helper 1

Th2:

T helper 2

TNF-α:

Tumor necrosis factor-α

Tregs:

Regulatory T cells

VCAM-1:

Vascular cell adhesion molecule-1

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Acknowledgments

This research was supported by grants from the Korean Society of Ginseng and the Korea Ginseng Cooperation (2012–2013) and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (2007–0054931 and 2014R1A2A1A11051240). This research was also supported by the Traditional Korean Medicine R&D program founded by the Ministry of Health & Welfare through the Korea Health Industry Development Institute (KHIDI) (HI13C0263).

Conflict of Interest

All the authors of this manuscript have no conflict of interest in this subject.

Authors’ Contributions

MJL performed the behavioral experiment, immunohistochemistry, PCR analysis, flow cytometry, and Western blots and prepared the figures. MJ and JHC assisted with behavioral and histological experiments and prepared the figures. BSC performed the histological experiment associated with semithin section. DYK, SKO, SHK, YSK, SO, JHL, BJC, and SYN commented about the treatment with KRGE, contributed to the interpretation of data, and supervised the project. IHC conceived all experiments, analyzed the results, and wrote the manuscript. All authors have read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Cancer Preventive Material Development, College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Min Jung Lee, Minhee Jang & Sung-Hoon Kim

  2. Department of Convergence Medical Sciences, College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Min Jung Lee, Minhee Jang, Jonghee Choi & Ik-Hyun Cho

  3. Institute of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Ik-Hyun Cho

  4. Department of Cosmetology, Hanseo University, Seosan, 356-706, Republic of Korea

    Byung Soo Chang

  5. Barrow Neurological Institute and St. Joseph’s Medical Center, Phoenix, AZ, 85013, USA

    Do Young Kim

  6. Central Research Institute, Korea Ginseng Corporation, Daejeon, 305-805, Republic of Korea

    Yi-Seong Kwak

  7. Department of Neuroscience and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, 158-710, Republic of Korea

    Seikwan Oh

  8. Department of Veterinary Anatomy, College of Veterinary Medicine, Konkuk University, Seoul, 143-701, Republic of Korea

    Jong-Hwan Lee & Byung-Joon Chang

  9. Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul, 143-701, Republic of Korea

    Seung-Yeol Nah

  10. Brain Korea 21 Plus Program, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Jonghee Choi & Ik-Hyun Cho

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  1. Min Jung Lee
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Lee, M.J., Jang, M., Choi, J. et al. Korean Red Ginseng and Ginsenoside-Rb1/-Rg1 Alleviate Experimental Autoimmune Encephalomyelitis by Suppressing Th1 and Th17 Cells and Upregulating Regulatory T Cells. Mol Neurobiol 53, 1977–2002 (2016). https://doi.org/10.1007/s12035-015-9131-4

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