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Bee Venom Acupuncture Alleviates Experimental Autoimmune Encephalomyelitis by Upregulating Regulatory T Cells and Suppressing Th1 and Th17 Responses

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Abstract

The protective and therapeutic mechanism of bee venom acupuncture (BVA) in neurodegenerative disorders is not clear. We investigated whether treatment with BVA (0.25 and 0.8 mg/kg) at the Zusanli (ST36) acupoints, located lateral from the anterior border of the tibia, has a beneficial effect in a myelin basic protein (MBP)68–82-induced acute experimental autoimmune encephalomyelitis (EAE) rat model. Pretreatment (every 3 days from 1 h before immunization) with BVA was more effective than posttreatment (daily after immunization) with BVA with respect to clinical signs (neurological impairment and loss of body weight) of acute EAE rats. Treatment with BVA at the ST36 acupoint in normal rats did not induce the clinical signs. Pretreatment with BVA suppressed demyelination, glial activation, expression of cytokines [interferon (IFN)-γ, IL-17, IL-17A, tumor necrosis factor-alpha (TNF-α), and IL-1β], chemokines [RANTES, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1α], and inducible nitric oxide synthase (iNOS), and activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB (p65 and phospho-IκBα) signaling pathways in the spinal cord of acute EAE rats. Pretreatment with BVA decreased the number of CD4+, CD4+/IFN-γ+, and CD4+/IL-17+ T cells, but increased the number of CD4+/Foxp3+ T cells in the spinal cord and lymph nodes of acute EAE rats. Treatment with BVA at six placebo acupoints (SP9, GB39, and four non-acupoints) did not have a positive effect in acute EAE rats. Interestingly, onset and posttreatment with BVA at the ST36 acupoint markedly attenuated neurological impairment in myelin oligodendrocyte glycoprotein (MOG)35–55-induced chronic EAE mice compared to treatment with BVA at six placebo acupoints. Our findings strongly suggest that treatment with BVA with ST36 acupoint could delay or attenuate the development and progression of EAE by upregulating regulatory T cells and suppressing T-helper (Th) 17 and Th1 responses. These results warrant further investigation of BVA as a treatment for autoimmune disorders of the central nervous system.

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Acknowledgments

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2007-0054931, 2010-0010858, and 2010-0026575). This study 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 authors of this manuscript have no conflict of interest relevant to this subject.

Authors’ Contributions

MJL performed the behavioral experiment, immunohistochemistry, PCR analysis, flow cytometry analysis, Western blot analysis, and prepared the figures. JHC and MJ assisted in behavioral experiments. GL and HJM commented on the flow cytometry analysis. WSC, JIK, YC, and SHK commented on treatment with BV/BVA. SJL, YJ, YC, and SHK 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 Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Min Jung Lee, Minhee Jang & Sung-Hoon Kim

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

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

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

    Jonghee Choi & Ik-Hyun Cho

  4. Department of Physiology, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Gihyun Lee

  5. Department of Neuroscience and Physiology, School of Dentistry, Seoul National University, Seoul, 110-799, Republic of Korea

    Hyun Jung Min & Sung Joong Lee

  6. Dental Research Institute, School of Dentistry, Seoul National University, Seoul, 110-799, Republic of Korea

    Hyun Jung Min & Sung Joong Lee

  7. Brain Korea 21 Plus Program, School of Dentistry, Seoul National University, Seoul, 110-799, Republic of Korea

    Hyun Jung Min & Sung Joong Lee

  8. Department of Rehabilitation Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Won-Seok Chung

  9. Department of Acupuncture and Moxibustion, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Jong-In Kim

  10. College of Veterinary Medicine, Jeju National University, Jeju, 690-756, Republic of Korea

    Youngheun Jee

  11. Applied Radiological Science Institute, Jeju National University, Jeju, 690-756, Republic of Korea

    Youngheun Jee

  12. Acupuncture and Meridian Science Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Younbyoung Chae

  13. Institute of Oriental Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Ik-Hyun Cho

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  1. Min Jung Lee
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Correspondence to Ik-Hyun Cho.

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Supplementary Data 1

Photograph showing the location of the ST36 acupoint, non-acupoints, and neurological abnormalities after immunization (A-E) The location of the ST36 acupoint and six placebo-acupoints. ST36 (Zusanli) acupoint is located 5 mm below and lateral to the anterior tubercle of the tibia (A and B). SP9 acupoint is located in a depression between the posterior border of the tibia and the gastrocnemius muscle near the knee joint or the inferior border of the medial condyle of the tibia (A and C). GB39 is located distal 4/5 points on the imaginary line connecting the lateral side of the knee and the lateral malleolus of the tibiofibula (A and B). NA1 is localized on the proximal edge of the patella (A), NA2 is located on the lower leg, 3 units lateral to and below ST36 (A and B), NA3 is localized in the gluteal region near the ischial tuberosity (D), and NA4 is localized on the base of the proximal tail, approximately 3 cm from the posterior border of the gluteus muscle in rats (E). The NA1-4 location was chosen as it does not coincide with any classically defined acupoint or meridian structure, and it is located on the hindlimb and tail of rats and mice. A, anterior view; B and E, lateral view; C, medial view; D, ventral view (PDF 126 kb)

Supplementary Data 2

Photograph showing the neurological abnormalities after immunization. (A-H) The scale of neurological abnormalities after immunization in acute EAE rats. Grade 0, absence of symptoms (A); Grade 0.5, partial loss of tail tonus (B and C); Grade 1, paralysis of the tail (D); Grade 2, paraparesis of the hindlimb (E); Grade 3, paraplesis (F); Grade 4, paraplegia (G); Grade 5, tetraplegia (H); Grade 6, death. (I-Q) The scale of neurological abnormalities after immunization in chronic EAE mice. Grade 0, absence of symptoms (I and J); Grade 1, partial loss of tail tonus (K); Grade 2, paralysis of the tail (L and M); Grade 3, paraparesis (N); Grade 4, paraplegia (O); Grade 5, tetraparesis (P); Grade 6, tetraplegia (Q); Grade 7, death (PDF 231 kb)

Supplementary Data 3

Treatment with BVA at the placebo-acupoints away from ST36 fails to alleviate neurological impairment and histopathological changes in the spinal cord (A) BVA treatment into the placebo-acupoints [NA3 (on the gluteal region near the ischial tuberosity) and NA4 (on the base of the proximal tail located approximately 3 cm from the posterior border of the gluteus muscle) as nonspecific acupoints away from ST36] was performed every 3 days from 20 min before immunization. Rats were scored daily until 21 days. Treatment with BVA did not improve the neurological impairment after immunization. Data are expressed as mean clinical scores ± SEM. (ANOVA test; *p < 0.01 and **p < 0.05 versus MBP + saline-treated rats). (B-S) Spinal cord sections obtained from rats in each group (n = 3-5) at day 15–16 post-immunization were analyzed with respect to the degree of demyelination by luxol fast blue stain (B-J) and the degree of recruitment/infiltration of immune cells by H & E stain (K-S). Treatment with BVA at the placebo-acupoints did not block demyelination (B-J) and recruitment/infiltration of immune cells (K-S) in the spinal cord of rats acute EAE. Panels F-I and O-R display high magnification micrographs of panels B-E and K-N marked with squares, respectively. Bars =100 μm. (ANOVA test; #p < 0.01 and ##p < 0.05 versus normal rats) (PDF 339 kb)

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Lee, M.J., Jang, M., Choi, J. et al. Bee Venom Acupuncture Alleviates Experimental Autoimmune Encephalomyelitis by Upregulating Regulatory T Cells and Suppressing Th1 and Th17 Responses. Mol Neurobiol 53, 1419–1445 (2016). https://doi.org/10.1007/s12035-014-9012-2

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  • DOI: https://doi.org/10.1007/s12035-014-9012-2

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