DOI QR코드

DOI QR Code

The effect of scopoletin on Aβ-induced neuroinflammatory response in microglial BV-2 cells

  • Mun, Hui-Jin (Dept. of Biomedical Laboratory Science, Konyang University) ;
  • Cho, Hyun-Jeong (Dept. of Biomedical Laboratory Science, Konyang University)
  • Received : 2020.05.14
  • Accepted : 2020.06.11
  • Published : 2020.06.30

Abstract

In this paper, it was confirmed that scopoletin inhibits neuroinflammation induced by amyloid beta oligomer (Aβ1-42) in microglial BV-2. The mechanisms of inflammatory cytokines and inflammatory mediators by scopoletin were identified. Alzheimer's disease is the most common neurodegenerative disease, but it is a disease whose specific etiology is unknown, and many studies are trying to solve it. We first measured the cell viability with the CCK-8 assay method to confirm that scopoletin and Aβ1-42 are toxic to BV-2 cells. Expression levels of interleukin 1 beta (IL-1β), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nuclear factor-κB (NF-κB) in inflammatory reactions induced by Aβ1-42 with western blot were analyzed. The ANOVA assay was used to compare protein expression differences between BV-2 cells treated with Aβ1-42 alone and BV-2 cells pretreated with Aβ1-42 and scopoletin. Therefore, this study suggested that scopoletin is worth developing as a neuroinflammatory protection agent for Alzheimer's disease in the future.

본 논문에서는 스코폴레틴이 알츠하이머병 신경염증보호제로서의 가능성을 제안하기 위해 미세아교세포 BV-2에서 아밀로이드베타 올리고머(Aβ1-42)로 유도된 염증을 억제하는지 확인하였다. 또한, 염증관련 사이토카인 및 염증매개인자가 어떠한 메커니즘으로 조절되는지 확인하였다. 알츠하이머병은 가장 흔한 신경 퇴행성 질환이지만, 특정 병인을 알 수 없는 질환이며, 이를 해결하기 위해 많은 연구에서 노력을 기울이고 있다. 우리는 먼저 스코폴레틴과 Aβ1-42가 BV-2 세포에 독성을 보이는지 확인하기 위해 CCK-8 assay 방법으로 세포 생존율을 측정하였다. Western Blot을 통해 Aβ1-42로 유도된 염증반응에서 interleukin 1 beta (IL-1β), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nuclear factor-κB (NF-κB)의 발현정도를 분석하였다. ANOVA 분석법을 통해 Aβ1-42를 단독 처리한 BV-2 세포와 스코폴레틴을 전 처리한 BV-2 세포에서 단백질 발현 차이를 비교하였다. 그 결과 스코폴레틴을 전 처리한 BV-2 세포에서 IL-1β, COX-2, iNOS, NF-κB 발현수준이 유의미하게 감소되었다 (p value < 0.05). 따라서 본 연구는 향후 스코폴레틴이 알츠하이머병의 신경염증보호제로서 개발 가치가 있음을 제시하였다.

Keywords

References

  1. Alzheimer's Association, "2020 Alzheimer's disease facts and figures", Alzheimer's and Dementia, Vol. 16, No. 3, pp. 391-460, Mar 2020, DOI: 10.1002/alz.12068
  2. Chandra Sekhar Kuruva, and P Hemachandra Reddy, "Amyloid Beta Modulators and Neuroprotection in Alzheimer's Disease: A Critical Appraisal", Drug Discovery Today, Vol. 22, pp. 223-233, Feb 2017, DOI: 10.1016/j.drudis.2016.10.010
  3. C. Cheignon, M..Tomas, D.Bonnefont-Rousselot, P. Faller, C. Hureau, and F. Collin, "Oxidative stress and the amyloid beta peptide in Alzheimer's disease", Redox Biology, Vol. 14, pp. 450-464, Apr 2018, DOI: 10.1016/j.redox.2017.10.014
  4. Saeed Sadigh-Eteghad, Babak Sabermarouf, Alireza Majdi, Mahnaz Talebi, Mehdi Farhoudi, and Javad Mahmoudi "Amyloid-Beta: A Crucial Factor in Alzheimer's Disease", Medical Principles and Practice, Vol. 24, No. 1, pp. 1-10, Nov 2014, DOI: 10.1159/000369101
  5. Barbara Mroczko, Magdalena Groblewska, Ala Litman-Zawadzka, Johannes Kornhuber, and Piotr Lewczuk, "Amyloid ${\beta}$ oligomers (A${\beta}$Os) in Alzheimer's disease", Journal of Neural Transmission, Vol. 125, No. 2, pp. 177-191, Feb 2018, DOI: 10.1007/s00702-017-1820-x
  6. David V. Hansen, Jesse E. Hanson, and Morgan Sheng, "Microglia in Alzheimer's disease", Journal of Cell Biololy, Vol. 217, No. 2, pp. 459-472, Feb 2018, DOI: 10.1083/jcb.201709069
  7. Francesca Regen, Julian Hellmann-Regen, Erica Costantini, and Marcella Reale, "Neuroinflammation and Alzheimer's Disease: Implications for Microglial Activation", Current Alzheimer Research, Vol. 14, No. 11, pp. 1140-1148, Nov 2017, DOI 10.2174/1567205014666170203141717
  8. Elizabeth E. Spangenberg, and Kim N. Green, "Inflammation in Alzheimer's disease: Lessons learned from microglia-depletion models", Brain, Behavior, and Immunity, Vol. 61, pp. 1-11, Mar 2017, DOI: 10.1016/j.bbi.2016.07.003
  9. Atsuko Katsumoto, Hideyuki Takeuchi, Keita Takahashi, and Fumiaki Tanaka, "Microglia in Alzheimer's Disease: Risk Factors and Inflammation", Frontiers in Neurology, Vol. 9, No. 978, Nov 2018, DOI: 10.3389/fneur.2018.00978
  10. Atish Kumar Sahoo, Jagnehswar Dandapat, Umesh Chandra Dash, and Satish Kanhar, "Features and outcomes of drugs for combination therapy as multi-targets strategy to combat Alzheimer's disease", Journal of Ethnopharmacology, Vol. 215, pp. 42-73, Apr 2018, DOI: 10.1016/j.jep.2017.12.015
  11. Devesh Tewari, Adrian M. Stankiewicz, Andrei Mocan, Archana N. Sah1,Nikolay T. Tzvetkov 5, Lukasz Huminiecki, Jaroslaw O. Horbanczuk, and Atanas G. Atanasov, "Ethnopharmacological Approaches for Dementia Therapy and Significance of Natural Products and Herbal Drugs", Front Aging Neuroscience, Vol. 10, No. 3, Feb 2018, DOI: 10.3389/fnagi.2018.00003
  12. Abhijit Dey, Raktim Bhattacharya, Anuradha Mukherjee, and Devendra Kumar Pandey, "Natural products against Alzheimer's disease: Pharmaco-therapeutics and biotechnological interventions", Biotechnology Advances, Vol. 35, No. 2, pp. 178-216, Mar-Apr 2017, DOI: 10.1016/j.biotechadv.2016.12.005
  13. Hrishikesh Mohan Revankar, Syed Nasir Abbas Bukhari, Gajjela Bharath Kumar, and Hua-Li Qin, "Coumarins scaffolds as COX inhibitors", Bioorganic Chemistry, Vol. 71, pp. 146-159, Apr 2017, DOI: 10.1016/j.bioorg.2017.02.001
  14. Mylena Andrea Oliveira Torres, Isadora de Fatima Braga Magalhaes, Renata Mondego-Oliveira, Joicy Cortez de Sa, Alessandra Lima Rocha, and Ana Lucia Abreu-Silva "One Plant, Many Uses: A Review of the Pharmacological Applications of Morinda citrifolia", Phytotherapy Research, Vol. 31, NO. 7, pp. 971-979, Jul 2017, DOI: 10.1002/ptr.5817
  15. Negin Ahmadi, Suhaila Mohamed, Heshu Sulaiman Rahman, and Rozita Rosli, "Epicatechin and scopoletin-rich Morinda citrifolia leaf ameliorated leukemia via anti‐inflammatory, anti-angiogen esis, and apoptosis pathways in vitro and in vivo", European Journal of Pharmacology, Vol. 43, No. 7, Jul 2019, DOI: 10.1111/jfbc.12868
  16. Gilbert Kirsch, Ahmed Bakr Abdelwahab, and Patrick Chaimbault "Natural and Synthetic Coumarins with Effects on Inflammation", Molecules, Vol. 21, No. 10, pp. 1322, Oct 2016, DOI: 10.3390/molecules21101322
  17. Shane A. Liddelow, Kevin A. Guttenplan, Laura E. Clarke, Frederick C. Bennett, Christopher J. Bohlen, Lucas Schirmer, Mariko L. Bennett, Alexandra E. Münch, Won-Suk Chung, Todd C. Peterson, Daniel K. Wilton, Arnaud Frouin, Brooke A. Napier, Nikhil Panicker, Manoj Kumar, Marion S. Buckwalter, David H. Rowitch, Valina L. Dawson, Ted M. Dawson, Beth Stevens, and Ben A. Barres, "Neurotoxic reactive astrocytes are induced by activated microglia", Nature, Vol. 541, No. 7638, pp. 481-487, Jan 2017, DOI: 10.1038/nature21029
  18. Kelly S. Kirkley, Katriana A. Popichak, Maryam F. Afzali, Marie E. Legare, and Ronald B. Tjalkens, "Microglia amplify inflam matory activation of astrocytes in manganese neurotoxicity", Journal of Neuroinflammation, Vol. 14, No. 1, pp. 99, May 2017, DOI: 10.1186/s12974-017-0871-0
  19. Darshpreet Kaur, Vivek Sharma, and Rahul Deshmukh, "Activ ation of microglia and astrocytes: a roadway to neuroinflamm ation and Alzheimer's disease", Inflammopharmacology, Vol. 27, No. 4, pp. 663-677, Aug 2019, DOI: 10.1007/s10787-019-00580-x
  20. Suzanne Hickman, Saef Izzy, Pritha Sen, Liza Morsett, and Joseph El Khoury, "Microglia in neurodegeneration", Nature Neuroscience, Vol. 21, No. 10, pp. 1359-1369, Oct 2018, DOI: 10.1038/s41593-018-0242-x
  21. Pei-Pei Guan and Pu Wang, "Integrated Communications Between cyclooxygenase-2 and Alzheimer's Disease", The FASEB Journal, Vol. 13, No. 1, pp. 13-33, Jan 2019, DOI: 10.1096/fj.201800355RRRR
  22. Magali Dumont and M. Flint Beal, "Neuroprotective strategies involving ROS in Alzheimer disease", Free Radical Biology and Medicine, Vol. 51, No. 5, pp. 1014-1026, Sep 2011, DOI: 10.1016/j.freeradbiomed.2010.11.026
  23. Rui Yang, Sha Liu, Jia Zhou, Shuhong Bu, and Jian Zhang, "Andrographolide attenuates microglia-mediated A$\beta$ neurotoxicity partially through inhibiting NF-$\kappa$B and JNK-MAPK signaling pathway", Immunopharmacology and Immunotoxicology, Vol. 39, NO. 5, pp. 276-284, Oct 2017, DOI: 10.1080/08923973.2017.1344989