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Molecular Neurobiology

, Volume 54, Issue 10, pp 7706–7721 | Cite as

Novel Neuroprotective Effects of Melanin-Concentrating Hormone in Parkinson’s Disease

  • Ji-Yeun Park
  • Seung-Nam Kim
  • Junsang Yoo
  • Jaehwan Jang
  • Ahreum Lee
  • Ju-Young Oh
  • Hongwon Kim
  • Seung Tack Oh
  • Seong-Uk Park
  • Jongpil Kim
  • Hi-Joon Park
  • Songhee Jeon
Article

Abstract

Acupuncture has shown the therapeutic effect on various neurodegenerative disorders including Parkinson’s disease (PD). While investigating the neuroprotective mechanism of acupuncture, we firstly found the novel function of melanin-concentrating hormone (MCH) as a potent neuroprotective candidate. Here, we explored whether hypothalamic MCH mediates the neuroprotective action of acupuncture. In addition, we aimed at evaluating the neuroprotective effects of MCH and elucidating underlying mechanism in vitro and in vivo PD models. First, we tested whether hypothalamic MCH mediates the neuroprotective effects of acupuncture by challenging MCH-R1 antagonist (i.p.) in mice PD model. We also investigated whether MCH has a beneficial role in dopaminergic neuronal protection in vitro primary midbrain and human neuronal cultures and in vivo MPTP-induced, Pitx3−/−, and A53T mutant mice PD models. Transcriptomics followed by quantitative PCR and western blot analyses were performed to reveal the neuroprotective mechanism of MCH. We first found that hypothalamic MCH biosynthesis was directly activated by acupuncture treatment and that administration of an MCH-R1 antagonist reverses the neuroprotective effects of acupuncture. A novel finding is that MCH showed a beneficial role in dopaminergic neuron protection via downstream pathways related to neuronal survival. This is the first study to suggest the novel neuroprotective action of MCH as well as the involvement of hypothalamic MCH in the acupuncture effects in PD, which holds great promise for the application of MCH in the therapy of neurodegenerative diseases.

Keywords

Parkinson’s disease Acupuncture Melanin-concentrating hormone (MCH) Lateral hypothalamus Dopamine neuroprotection 

Notes

Acknowledgements

This work was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (No. HI13C0540).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2016_258_Fig7_ESM.gif (30 kb)
Supplemental Figure 1

Distribution of MCH neurons expressing c-Fos after acupuncture treatment. MCH cell distribution in the LH, PF, DMH and ZI (open circles). Double-labelled c-Fos + ⁄ MCH+cells (filled triangles) distinguished from single-labelled MCH+cells (open circles) in one Control, MPTP, MPTP+AP and MPTP+CP representative brain (n = 5 per group). f, fornix; PF, perifornical area; DMH, dorsomedial hypothalamus; LH, lateral hypothalamus; ZI, zona incerta;. Grey box (650 × 650 μm) represents the counting area of MCH Magnification bar, 500 μm. (GIF 30 kb)

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High Resolution Image (TIFF 890 kb)
12035_2016_258_Fig8_ESM.gif (113 kb)
Supplemental Figure 2

Effects of MCH on the survival and maintenance of midbrain dopamine neurons. (A) Methodology used to assess the effect of MCH on primary midbrain dopaminergic neurons. Primary midbrains containing the SN pars compacta (SNpc) and VTA were prepared from postnatal day 1 mice, and the cultures were treated with MCH with or without TC-MCH7c (MCH receptor type 1 antagonist) 5 days after plating. (B and C) Phase contrast images (B) and the number of dopaminergic neurons (C) in the control, MCH-, and MCH+TC-MCH7c-treated midbrain dopamine neurons (n = 3 per group). (D) Immunostaining for the neuronal markers TUJ-1 and MAP-2 in MCH- and MCH + TC-MCH7c-treated dopaminergic neurons. (E) Number of dopaminergic neurons among midbrain dopaminergic neurons treated with different concentrations (n = 5 per group). (F) qRT-PCR analysis of dopaminergic neuronal markers in control and MCH-treated dopaminergic neurons (n = 3 per group). (G) qRT-PCR analysis of dopaminergic neuronal markers in dopaminergic neurons treated with different concentrations of MCH (n = 3 per group). Scale bar, 100 μm. Data are expressed as mean ± SEM. * P < 0.05, ** P < 0.01, and *** P < 0.001 vs. control group; ††† P < 0.001 vs. MCH group in one-way ANOVA followed by a Newman-Keuls test (C, E, and G) or Student’s t test (F). (GIF 112 kb)

12035_2016_258_MOESM2_ESM.tif (3.2 mb)
High Resolution Image (TIFF 3292 kb)
12035_2016_258_Fig9_ESM.gif (16 kb)
Supplemental Figure 3

Effect of MCH on body weight and food intake. (A) Changes in body weight of control, MCH, AP, and AP+TC-MCH7c groups at the end of the experiment (day 12) (n=3 per group). (B) Total weight gain and total food intake were examined for 4 weeks in synuclein A53T Tg mice (n = 3 per group). Data are expressed as mean ± SEM. Statistical comparisons were made by one-way ANOVA or Student’s t-test. (GIF 15 kb)

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High Resolution Image (TIFF 408 kb)
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Supplemental Figure 4

Neuroprotective effects of MCH treatment in differentiated SH-SY5Y cells. (A) Cell death induced by 6-OHDA (100 μM) was prevented after 50 or 100 nM MCH treatment. (B-D) Increased levels of pp38 and pIκBα after 6-OHDA administration were diminished after 100 nM MCH treatment (n = 4 per group). Data represent the mean ± SEM. ** P < 0.01, *** P < 0.001 vs. control group, ## P < 0.01, ### P < 0.001 vs. 6-OHDA group via one-way ANOVA followed by Newman-Keuls test. (GIF 35 kb)

12035_2016_258_MOESM4_ESM.tif (1007 kb)
High Resolution Image (TIFF 1007 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ji-Yeun Park
    • 1
    • 2
  • Seung-Nam Kim
    • 1
    • 3
  • Junsang Yoo
    • 4
  • Jaehwan Jang
    • 1
  • Ahreum Lee
    • 1
    • 5
  • Ju-Young Oh
    • 1
    • 5
  • Hongwon Kim
    • 4
  • Seung Tack Oh
    • 4
  • Seong-Uk Park
    • 1
    • 6
  • Jongpil Kim
    • 4
  • Hi-Joon Park
    • 1
    • 5
  • Songhee Jeon
    • 7
  1. 1.Integrative Parkinson’s Disease Research Group, Acupuncture & Meridian Science Research CenterKyung Hee UniversitySeoulRepublic of Korea
  2. 2.College of Korean MedicineDaejeon UniversityDaejeonRepublic of Korea
  3. 3.Department of Meridian and AcupointDongguk UniversityGoyang-siRepublic of Korea
  4. 4.Department of Biomedical EngineeringDongguk UniversitySeoulRepublic of Korea
  5. 5.Department of Korean Medical Science, Graduate School of Korean MedicineKyung Hee UniversitySeoulRepublic of Korea
  6. 6.Stroke and Neurological Disorders CenterKyung Hee University Hospital at GangdongSeoulRepublic of Korea
  7. 7.Department of Biomedical Sciences, Center for Creative Biomedical ScientistsChonnam National UniversityGwangjuRepublic of Korea

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