Efek Asam Klorogenat pada Ekspresi Mrna IL-6 dan CD86 Lobus Frontal Tikus Model Diabetes Mellitus

Authors

  • Fauziyatul Munawaroh Fakultas Kedokteran, IPB University
  • Aisyah Amanda Hanif Fakultas Kedokteran, IPB University
  • Asri Ragil Kemuning Fakultas Kedokteran, IPB University
  • Iffa Mutmainah Fakultas Kedokteran, IPB University
  • Yenny Rachmawati Fakultas Kedokteran, IPB University
  • Naufal Muharam Nurdin 1. Fakultas Kedokteran, IPB University 2. Departemen Gizi Masyarakat, Fakultas Ekologi Manusia, IPB University

DOI:

https://doi.org/10.20961/plexus.v3i4.1815

Keywords:

Asam Klorogenat, CGA, Neuroinflamasi, Diabetes Mellitus

Abstract

Pendahuluan: Diabetes Mellitus (DM) merupakan penyakit kronik dengan berbagai komplikasi, salah satunya yaitu Encephalopati Diabetikum (ED). Hiperglikemia pada DM akan mengakibatkan neuroinflamasi melalui jalur M1 proinflamatorik. Beberapa agen proinflamatori akan meningkat dengan aktifnya jalur ini, seperti IL-6. Neuroglia kemudian teraktivasi dan mengekspresikan CD86 pada membran sel. Asam klorogenat (CGA) merupakan senyawa polyphenol pada kopi  yang  memiliki  efek antiinflamasi.  Tujuan penelitian ini adalah untuk memperjelas efek CGA pada aktivasi mikroglia jalur M1 dengan melihat ekspresi mRNA IL-6 dan CD86 pada lobus frontal tikus dengan model DM.

Metode: 24 ekor tikus jantan secara acak dibagi menjadi enam kelompok yaitu :  kontrol,   DM 1,5 bulan dan DM 2 bulan,  dan kelompok dengan pemberian  CGA dengan  tiga  dosis  berbeda  (CGA1,  CGA2,  CGA3).  Jaringan lobus frontal diambil untuk analisa ekspresi mRNA IL-6 dan CD86 menggunakan RT-PCR.
Hasil: Ekspresi mRNA IL-6 lobus frontal berbeda signifikan antara kelompok kontrol dengan DM1,5 (p=0.010); kontrol dengan DM2 (p=0.001); kelompok DM2 dengan CGA2 (p=0.028). Ekspresi mRNA CD86 lobus frontal trdapat perbedaan signifikan antara kelompok kontrol dengan semua kelompok DM, baik dengan CGA atau tanpa CGA (p<0.05). Kelompok DM2 berbeda signifikan dengan kelompok CGA2 (p=0.000) dan kelompok CGA3 (p=0,000).

Kesimpulan: Ekspresi mRNA penanda jaras proinflamatorik M1 (IL-6 dan CD86) pada neuroinflamasi lobus frontal akibat DM lebih rendah setelah pemberian CGA dengan dosis 25 mg/KgBB.

References

Amano, M., Nakayama, M., & Kaibuchi, K. (2010). Rho-Kinase/ROCK: A Key Regulator of the Cytoskeleton and Cell Polarity. Cytoskeleton, 67, 545–554. doi: 10.1002/cm.20472

Beurel, E., Grieco, S.F., & Jope, R.S. (2015). Diseases. Pharmacol Ther. Author April: 114–131. doi:10.1017/S0003598X00113821

Camfield, D.A., Silber, B.Y., Scholey, A.B., Nolidin, K., Goh, A., & Stough, C. (2013). A randomised placebo-controlled trial to differentiate the acute cognitive and mood effects of chlorogenic acid from decaffeinated coffee. PLoS ONE , 8, Article e82897. https://doi.org/10.1371/journal.pone.0082897

Cropley, V., Croft, R., Silber, B., Neale, C., Scholey, A., Stough, C., & Schmitt, J. (2012). Does coffee enriched with chlorogenic acids improve mood and cognition after acute administration in healthy elderly: A pilot study. Psychopharmacology, 219, 737–749. Doi: 10.1007/s00213-011-2395-0

Chen, H., O’Reilly, E.J., & Schwarzschild, M.A. (2008). Ascherio, A. Peripheral Inflammatory Biomarkers and Risk of Parkinson’s Disease. Am. J. Epidemiol., 167, 90–95. 10.1093/aje/kwm260

Chen, J., Sun, Z., Jin, M., Tu, Y., Wang, S., Yang, X., Chen, Q., Zhang, X., Han, Y., & Pi, R. (2017). Inhibition of AGEs/RAGE/Rho/ROCK Pathway Suppresses Non-Specific Neuroinflammation by Regulating BV2 Microglial M1/M2 Polarization through the NF-KB Pathway. J. Neuroimmunol., 305, 108–114. DOI: 10.1016/j.jneuroim.2017.02.010

Fan, Z., Zhang, W., Cao, Q., Zou, L., Fan, X., Qi, C., Yan, Y., Song, B., & Wu, B. (2022). JAK2/STAT3 Pathway Regulates Microglia Polarization Involved in Hippocampal Inflammatory Damage Due to Acute Paraquat Exposure. Ecotoxicol. Env. Saf, 234, 113372. https://doi.org/10.1016/j.ecoenv.2022.113372

Gao, J., He, X., Ma, Y., Zhao, X., Hou, X., Hao, E., Deng, J., & Bai, G. (2018). Chlorogenic acid targeting of the AKT PH domain activates AKT/GSK3β/FOXO1 signaling and improves glucose metabolism. Nutrients 10. doi:10.3390/nu10101366

Giugliano, D., Ceriello, A., & Esposito, K. (2008). Glucose metabolism and hyperglycemia. Am. J. Clin. Nutr. 87: 217–222. doi:10.1093/ajcn/87.1.217s

Glovaci, D., Fan, W., & Wong, N.D. (2019). Epidemiology of Diabetes Mellitus and Cardiovascular Disease. Curr. Cardiol. Rep. 21: 1–8. doi:10.1007/s11886-019-1107-y

Gonthier, M.P., Verny, M.A., Besson, C., Rémésy, C., & Scalbert, A. (2003). Chlorogenic acid bioavailability largely depends on its metabolism by the gut microflora in rats. Am. Soc. Nutr. Sci. 133: 1853–1859. doi:10.1093/jn/133.6.1853

Gul, Z., Demircan, C., Bagdas, D., & Buyukuysal, R.L. (2016). Protective Effects of Chlorogenic Acid and its Metabolites on Hydrogen Peroxide-Induced Alterations in Rat Brain Slices: A Comparative Study with Resveratrol. Neurochem. Res., 41, 2075–2085. DOI:10.1007/s11064-016-1919-8

Heitman, E., & Ingram, D.K. (2014). Cognitive and neuroprotective effects of chlorogenic acid. Nutr. Neurosci. 1–6. DOI: 10.1179/1476830514Y.0000000146

Isik, S., Yeman, KB., Akbayir, R., Seyhali, R., Arpaci, T. (2023). Microglia Mediated Neuroinflammation in Parkinson's Disease. Cells., 5;12(7):1012. doi: 10.3390/cells12071012.

Kaidanovich-Beilin, O., & Woodgett, J.R. (2011). GSK-3: Functional Insights from Cell Biology and Animal Models. Front. Mol. Neurosci. 4: 1–25. doi:10.3389/fnmol.2011.00040

Kwon, S., Lee, H., Kim, J., Hong, S., Kim, H., Jo, T., et al. (2010). Neuroprotective effects of chlorogenic acid on scopolamine-induced amnesia via anti-acetylcholinesterase and anti-oxidative activities in mice. Eur. J. Pharmacol. 649: 210–217. doi:10.1016/j.ejphar.2010.09.001

Lee, K., Lee, J.S., Jang, H.J., Kim, S.M., Chang, M.S., Park, S.H., Kim, K.S., Bae, J., Park, J.W., Lee, B., et al. (2012). Chlorogenic acid ameliorates brain damage and edema by inhibiting matrix metalloproteinase-2 and 9 in a rat model of focal cerebral ischemia. Eur. J. Pharmacol., 689, 89–95. DOI: 10.1016/j.ejphar.2012.05.028

Lawrence, T., & Natoli, G. (2011). Transcriptional Regulation of Macrophage Polarization: Enabling Diversity with Identity. Nat. Rev. Immunol., 11, 750–761. DOI: 10.1038/nri3088

Mira, A., Yamashita, S., Katakura, Y., & Shimizu, K. (2015). In vitro neuroprotective activities of compounds from Angelica shikokiana Makino. Molecules, 20, 4813–4832. https://doi.org/10.3390/molecules20034813

Moheet, A., Mangia, S., & Seaquist, E.R. (2015). Impact of diabetes on cognitive function and brain structure. Ann. N. Y. Acad. Sci. 1353: 60–71. doi:10.1111/nyas.12807

Mount, M.P., Lira, A., Grimes, D., Smith, P.D., Faucher, S., Slack, R., Anisman, H., Hayley, S., & Park, D.S. (2007). Involvement of Interferon-in Microglial-Mediated Loss of Dopaminergic Neurons. J. Neurosci., 27, 3328. DOI: 10.1523/JNEUROSCI.5321-06.2007

Naveed, M., Hejazi, V., Abbas, M., Kamboh, A.A., Khan, G.J., Shumzaid, M., et al. (2018). Chlorogenic acid (CGA): A pharmacological review and call for further research. Biomed. Pharmacother. 97: 67–74. doi:10.1016/j.biopha.2017.10.064

Nguyen, V., Taine, E.G., Meng, D., Cui, T., & Tan, W. (2024). Chlorogenic Acid: A Systematic Review on the Biological Functions, Mechanistic Actions, and Therapeutic Potentials. Nutrients, 23;16(7):924. doi: 10.3390/nu16070924

Ohnishi, R., Ito, H., Iguchi, A., Shinomiya, K., Kamei, C., Hatano, T., & Yoshida, T. (2006). Effects of chlorogenic acid and its metabolites on spontaneous locomotor activity in mice. Biosci. Biotechnol. Biochem., 70, 2560–2563. DOI: 10.1271/bbb.60243

Piatkowska-Chmiel, I., Herbet, M., Gawronska-Grzywacz, M., Ostrowska-Lesko, M., & Dudka, J., (2021). The role of molecular and inflammatory indicators in the assessment of cognitive dysfunction in a mouse model of diabetes. Int. J. Mol. Sci. 22. doi:10.3390/ijms22083878

Sandireddy, R., Yerra, V.G., Areti, A., Komirishetty, P., & Kumar, A. (2014). Neuroinflammation and oxidative stress in diabetic neuropathy: Futuristic strategies based on these targets. Int. J. Endocrinol. 2014. doi:10.1155/2014/674987

Shen, W., Qi, R., Zhang, J., Wang, Z., Wang, H., Hu, C., Zhao, Y., Bie, M., Wang, Y., Fu, Y., et al. (2012). Chlorogenic acid inhibits LPS-induced microglial activation and improves survival of dopaminergic neurons. Brain Res. Bull., 88, 487–494. DOI: 10.1016/j.brainresbull.2012.04.010

Souder, D.C., & Anderson, R.M. (2019). An expanding GSK3 network: implications for aging research. GeroScience 41: 369–382. doi:10.1007/s11357-019-00085-z

Stankiewicz, T.R., & Linseman, D.A. (2014). Rho Family GTPases: Key Players in Neuronal Development, Neuronal Survival, and Neurodegeneration. Front. Cell. Neurosci., 8, 314. DOI: 10.3389/fncel.2014.00314

Varinou, L., Ramsauer, K., Karaghiosoff, M., Kolbe, T., Pfeffer, K., Müller, M., & Decker, T. (2003) Phosphorylation of the Stat1 Transactivation Domain Is Required for Full-Fledged IFN--Dependent Innate Immunity. Immunity, 19, 793–802. DOI: 10.1016/s1074-7613(03)00322-4

Wang, X., Fan, X., Yuan, S., Jiao, W., Liu, B., Cao, J., & Jiang, W. (2017). Chlorogenic acid protects against aluminium-induced cytotoxicity through chelation and antioxidant actions in primary hippocampal neuronal cells. Food Funct., 8, 2924–2934. https://doi.org/10.1039/C7FO00659D

Wang, C., Song, S., Zhang, Y., Ge, Y., Fang, X., Huang, T., Du, J., & Gao, J. (2015). Inhibition of the Rho/Rho Kinase Pathway Prevents Lipopolysaccharide-Induced Hyperalgesia and the Release of TNF-and IL-1 in the Mouse Spinal Cord. Sci. Rep., 5, 14553. DOI: 10.1038/srep14553

Xin, P., Xu, X., Deng, C., Liu, S., Wang, Y., Zhou, X., Ma, H., Wei, D., & Sun, S. (2020). The Role of JAK/STAT Signaling Pathway and Its Inhibitors in Diseases. Int. Immunopharmacol., 80, 106210. DOI: 10.1016/j.intimp.2020.106210

Yang, Z., & Wang, K.K.W. (2015). Glial fibrillary acidic protein: From intermediate filament assembly and gliosis to neurobiomarker. Trends Neurosci. 38: 364–374. doi:10.1016/j.tins.2015.04.003

Yao, J., Peng, S., Xu, J., & Fang, J. (2019). Reversing ROS-mediated neurotoxicity by chlorogenic acid involves its direct antioxidant activity and activation of Nrf2-ARE signaling pathway. Biofactors, 45, 616–626. DOI: 10.1002/biof.1507

Downloads

Published

2024-10-01

Issue

Section

Articles