Skip to main content

Advertisement

SpringerLink
Log in

Immunomodulatory and therapeutic role of Cinnamomum verum extracts in collagen-induced arthritic BALB/c mice

  • Original Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Ethnopharmacological relevance

Cinnamomum verum (CV), also known as ‘Dalchini’, is the dry bark of the Cinnamomum verum (L.) plant, and has been used as a traditional Pakistani medicine to alleviate pain and inflammation in patients suffering from arthritic rheumatism. It contains alkaloids, triterpenes, Cinnamaldehyde and other volatile oils. The aim of the present study was to investigate the underlying biological effect of ethyl alcohol (EtOH) and methyl alcohol (MeOH) extracts from CV on collagen type-II induced arthritic (CIA) mice.

Materials and methods

Gas chromatography mass spectrophotometry was used to perform fingerprinting identification of the EtOH and MeOH extracts. CIA mice model was established by subdermal injections of type-II bovine collagen (CII) on the 1st, 8th and 14th day of the experiment. Ethyl alcohol extract and methyl alcohol extract (1 mg/KgBW, 2 mg/KgBW and 4 mg/KgBW), was orally administered from the 15th day onwards for 2 weeks. Progression of oedema and joint inflammation was measured in the paws using a digital Vernier calliper every 3 days from day 1 till the end of the experiment. The oxidative scavenging ability of cinnamaldehyde was evaluated using a DPPH assay. Similarly, the nitrogen free radical (NOS) production of isolated lymphocytes was evaluated using Greiss’s method. The spleen index was calculated and knee joint changes were observed by histopathological sectioning. Western blot analysis was performed on peripheral blood derived serum for CII, CAPN1, TNFα and NFATc3.

Results

Extracts were shown to be enriched in trans-cinnamaldehyde and its analogues. Extracts showed good ameliorative effects (p < 0.05) after day 2 of treatment. A greater therapeutic role was observed for the 4 mg/kgBW dosage of the methanolic extract (p < 0.01). Swelling in the spleen was greatly reduced along with the generation of free radicals by lymphocytes, post treatment. There was also an inhibitory role by the extracts on NFATc3 (p < 0.05), TNF-Alpha (p < 0.05), CAII (p < 0.05) and mCalpain (p < 0.05) all proteins involved in RA.

Conclusion

In this study, it has been demonstrated that administration of CV has a therapeutic potential on CIA. The data suggest that CV could have a potential role in the treatment of RA patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Ahmed S, Hasan M (2016) Muslim heritage in medicine: a concise review on Greco-Arabic contribution. J Pharmacogn Phytother 5(4):273–283

    Google Scholar 

  • Akram M, Usmanghani K, Ahmed I, Azhar I, Hamid A, Pak J (2014) Comprehensive review on therapeutic strategies of gouty arthritis. Pharm Sci 27:1575–1582

    Google Scholar 

  • Ali SM, Khan AA, Ahmed I, Musaddiq M, Ahmed KS, Polasa H, Rao LV, Habibullah CM, Sechi LA, Ahmed N (2005) Antimicrobial activities of Eugenol and Cinnamaldehyde against the human gastric pathogen Helicobacter pylori. Ann Clin Microbiol 4(1):1

    Article  Google Scholar 

  • Alver A, Sentürk A, Çakirbay H, Mentese A, Gökmen F, Keha EE, Uçar F (2011) Carbonic anhydrase II autoantibody and oxidative stress in rheumatoid arthritis. Clin Biochem 44(17):1385–1389

    Article  CAS  PubMed  Google Scholar 

  • Bopp T, Palmetshofer A, Serfling E, Heib V, Schmitt S, Richter C, Stassen M (2001) NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4 + T lymphocytes by CD4 + CD25 + regulatory T cells. J Exp Med 201(2):181–187

    Article  Google Scholar 

  • Das Kajari, Samanta Luna, Chainy GBN (2000) A modified spectrophotometric assay of superoxide dismutase using nitrite formation by superoxide radicals. Ind J Biochem Biophys 37(3):201–204

    CAS  Google Scholar 

  • Doan T, Massarotti E (2015) Rheumatoid arthritis: an overview of new and emerging therapies. J Clin Pharmacol 45(7):751–762

    Article  Google Scholar 

  • Efthimiou P, Kukar M (2010) Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efficacy of commonly used modalities. Rheum Int 30:571–586

    Article  Google Scholar 

  • Eijaz Sana, Salim Asmat, Waqar Muhammad Anwar (2014) Possible molecular targets of Cinnamon in the insulin signaling pathway. J Biochem Technol 5(2):708–717

    Google Scholar 

  • Elahi EN, Wright Z, Hinselwood D, Hotchkiss SA, Basketter DA, Smith Pease CK (2004) Protein binding and metabolism influence the relative skin sensitization potential of cinnamic compounds. Chem Res Tox 17(3):301–310

    Article  CAS  Google Scholar 

  • Harput US, Saracoglu I, Ogihara Y (2014) Stimulation of lymphocyte proliferation and inhibition of nitric oxide production by aqueous Urtica dioica extract. Phytother Res 19:346–348

    Article  Google Scholar 

  • Hasani-Ranjbar S, Larijani B, Abdollahi M (2009) A systematic review of the potential herbal sources of future drugs effective in oxidant-related diseases. Inflamm Allergy Drug Targets 8(1):2–10

    Article  CAS  PubMed  Google Scholar 

  • Horiuchi T, Mitoma H, Harashima SI, Tsukamoto H, Shimoda T (2010) Transmembrane TNF-α: structure, function and interaction with anti-TNF agents. Rheumatology 49(7):1215–1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Impellizzeri D, Esposito E, Di Paola R, Ahmad A, Campolo M, Peli A, Morittu VM, Britti D, Cuzzocrea S (2013) Palmitoylethanolamide and luteolin ameliorate development of arthritis caused by injection of collagen type II in mice. Arthritis Res Ther 15(6):4055

    Article  Google Scholar 

  • Ishikawa H, Nakagawa Y, Shimizu K, Nishihara H, Matsusue Y, Nakamura T (1999) Inflammatory cytokines induced down-regulation of m-calpain mRNA expression in fibroblastic synoviocytes from patients with osteoarthritis and rheumatoid arthritis. Biochem Biophys Res Commun 266(2):341–346

    Article  CAS  PubMed  Google Scholar 

  • Iwaki-Egawa S, Matsuno H, Yudoh K, Nakazawa F, Miyazaki K, Ochiai A, Watanabe Y (2004) High diagnostic value of anticalpastatin autoantibodies in rheumatoid arthritis detected by ELISA using human erythrocyte calpastatin as antigen. J Rheumatol 31(1):17–22

    CAS  PubMed  Google Scholar 

  • Jawale A, Datusalia AK, Bishnoi M, Sharma SS (2016) Reversal of diabetes-induced behavioral and neurochemical deficits by Cinnamaldehyde. Phytomed 23:923–930

    Article  CAS  Google Scholar 

  • Khan A, Safdar M, Khan MMA, Khattak KN, Anderson RA (2003) Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care 26(12):3215–3218

    Article  PubMed  Google Scholar 

  • Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, Kashiwazaki S (1996) Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Min Res 11(1):88–95

    Article  CAS  Google Scholar 

  • Kotlyarov A, Neininger A, Schubert C, Eckert R, Birchmeier C, Volk HD, Gaestel M (1999) MAPKAP kinase 2 is essential for LPS-induced TNF-a biosynthesis. Nat Cell Biol 1(2):94–97

    Article  CAS  PubMed  Google Scholar 

  • Li YQ, Kong DX, Wu H (2013) Analysis and evaluation of essential oil components of cinnamon barks using GC–MS and FTIR spectroscopy. Ind Crops Prod 41:269–278

    Article  CAS  Google Scholar 

  • López-Rodríguez C, Aramburu J, Rakeman AS, Rao A (1999) NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun. Proc Nat Acad Sci 96(13):7214–7219

    Article  PubMed  PubMed Central  Google Scholar 

  • Macian F (2005) NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5(6):472–484

    Article  CAS  PubMed  Google Scholar 

  • Madhavadas S, Subramanian S (2016) Cognition enhancing effect of the aqueous extract of Cinnamomum zeylanicum on non-transgenic Alzheimer’s disease rat model: Biochemical, histological, and behavioural studies. Nutr Neurosci 10:1–12

    Google Scholar 

  • Mahmood T, Yang PC (2012) Western blot: technique, theory, and trouble shooting. N Am J Med Sci 4(9):429–434. doi:10.4103/1947-2714.100998

    Article  PubMed  PubMed Central  Google Scholar 

  • Martinez GJ, Hu J, Pereira R, Crampton J, Togher S, Bild N, Crotty S, Rao A (2016) NFAT transcription factors promote the generation of follicular helper T cells in response to acute viral infection. J Immunol 196:58

    Article  Google Scholar 

  • Ménard HA, El-Amine M (1996) The calpain-calpastatin system in rheumatoid arthritis. Immunol Today 17(12):545–547

    Article  PubMed  Google Scholar 

  • Mishra A, Bhatti R, Singh A, Ishar MPS (2010) Ameliorative effect of the cinnamon oil from Cinnamomum zeylanicum upon early stage diabetic nephropathy. Planta Med 76(05):412–417

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa T, Yuan J (2000) Cross-talk between two cysteine protease families activation of caspase-12 by calpain in apoptosis. J Cell Biol 150(4):887–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naveed R, Iftikhar H, Abdul T, Muhammad T, Moazur R, Sohail H, Shahid M, Abu Baker S, Mazhar I (2013) Antimicrobial activity of the bioactive components of essential oils from Pakistani spices against Salmonella and other multi-drug resistant bacteria. BMC Complement Altern Med 13(1):1

    Article  Google Scholar 

  • Oh-hora M, Rao A (2008) Calcium signaling in lymphocytes. Curr Opin Imunol 20(3):250–258

    Article  CAS  Google Scholar 

  • Okazaki K, Chiba T (2002) Autoimmune related pancreatitis. Gut 51(1):1–4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parasuraman S, Gan ST, Sokkalingam AD (2014) Polyherbal formulation: concept of Ayurveda. Pharmacogn Rev 8(16):73

    Article  PubMed  PubMed Central  Google Scholar 

  • Perng DS, Tsai YH, Cherng J, Kuo CW, Shiao CC, Cherng JM (2016) Discovery of a novel anti-cancer agent targeting both topoisomerase I and II in hepatocellular carcinoma Hep 3B cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde. J Drug Targ 24(7):624–634

    Article  CAS  Google Scholar 

  • Piguet PF, Grau GE, Vesin C, Loetscher H, Gentz R, Lesslauer W (1992) Evolution of collagen arthritis in mice is arrested by treatment with anti-tumour necrosis factor (TNF) antibody or a recombinant soluble TNF receptor. Immunology 77(4):510

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qidwai W, Alim SR, Dhanani RH, Jehangir S, Nasrullah A, Raza A (2003) Use of folk remedies among patients in Karachi Pakistan. J Ayub Med Coll Abbottabad 15(2):31–33

    PubMed  Google Scholar 

  • Rao A, Luo C, Hogan PG (1997) Transcription factors of the NFAT family: regulation and function. Ann Rev Immunol 15(1):707–747

    Article  CAS  Google Scholar 

  • Rengarajan J, Tang B, Glimcher LH (2002) NFATc2 and NFATc3 regulate TH2 differentiation and modulate TCR-responsiveness of naive TH cells. Nat Immunol 3(1):48–54

    Article  CAS  PubMed  Google Scholar 

  • Schägger H (2006) Tricine–SDS-PAGE. Nat Prot 1:16–22

    Article  Google Scholar 

  • Seki NOBUO, Sudo Y, Mizuhara HIDEKAZU, Orito KEIKO, Imasaki AIKO, Ono S, Hamaoka T, Senoh H, Fujiwara H (1992) Type II collagen-induced murine arthritis: induction of arthritis depends on antigen-presenting cell function as well as susceptibility of host to an anticollagen immune response. J Immunol 148(10):3093–3099

    CAS  PubMed  Google Scholar 

  • Sharma Om P, Bhat Tej K (2009) DPPH antioxidant assay revisited. Food Chem 113(4):1202–1205

    Article  CAS  Google Scholar 

  • Shinwari ZK (2010) Medicinal plants research in Pakistan. J Med Plants Res 4:161–176

    Google Scholar 

  • Smith MA, Schnellmann RG (2001) Calpains, mitochondria, and apoptosis. Card Res 96(1):32–37

    Article  Google Scholar 

  • Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Taniguchi T (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3(6):889–901

    Article  CAS  PubMed  Google Scholar 

  • Teitelbaum SL, Tondravi MM, Ross FP (1997) Osteoclasts, macrophages, and the molecular mechanisms of bone resorption. J leuk Biol 61(4):381–388

    Article  CAS  Google Scholar 

  • Tulini FL, Souza VB, Echalar-Barrientos MA, Thomazini M, Pallone EM, Favaro-Trindade CS (2016) Development of solid lipid microparticles loaded with a proanthocyanidin-rich cinnamon extract (Cinnamomum zeylanicum): potential for increasing antioxidant content in functional foods for diabetic population. Food Res Int 85:10–18

    Article  CAS  Google Scholar 

  • Tuzcu Z, Orhan C, Sahin N, Juturu V, Sahin K (2017) Cinnamon polyphenol extract inhibits hyperlipidemia and inflammation by modulation of transcription factors in high-fat diet-fed rats. Oxid Med Cell Longev 2017:Article ID 1583098. doi:10.1155/2017/1583098

  • Verdrengh M, Carlsten H, Ohlsson C, Tarkowski A (2007) Addition of bisphosphonate to antibiotic and anti-inflammatory treatment reduces bone resorption in experimental Staphylococcus aureus-induced arthritis. J Orth Res 25(3):304–310

    Article  CAS  Google Scholar 

  • Vetal S, Bodhankar SL, Mohan V, Thakurdesai PA (2013) Anti-inflammatory and anti-arthritic activity of type-A procyanidine polyphenols from bark of Cinnamomum zeylanicum in rats. Food Sci Hum Wellness 2(2):59–67

    Article  Google Scholar 

  • Vossenaar ER, Després N, Lapointe E, van der Heijden A, Lora M, Senshu T, Ménard HA (2004) Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res Ther 6(2):R142–R150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilkins BJ, De Windt LJ, Bueno OF, Braz JC, Glascock BJ, Kimball TF, Molkentin JD (2002) Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediated cardiac hypertrophic growth. Mol Cell Biol 22(21):7603–7613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang YH, Morand EF, Getting SJ, Paul-Clark M, Liu DL, Yona S, Flower RJ (2004) Modulation of inflammation and response to dexamethasone by Annexin 1 in antigen-induced arthritis. Arthritis Rheum 50(3):976–984

    Article  CAS  PubMed  Google Scholar 

  • Yang K, Tong L, Chen C, Zhang P, Pi H, Ruan H, Wu J (2013) Therapeutic effects of extracts from Radix Toddaliae Asiaticae on collagen-induced arthritis in Balb/c mice. J Ethnopharm 146(1):355–362

    Article  CAS  Google Scholar 

  • Zaidi SF, Aziz M, Muhammad JS, Kadowaki M (2015) Diverse pharmacological properties of Cinnamomum cassia: a review. Pak J Pharm Sci 28:3

    Google Scholar 

  • Zia-UL-Haq M, Shahid SA, Khan BA, Imran I, Qayum M, Akhter M, Khan Z, Muhammed S (2012) Nematicidal potential of selected flora of Pakistan. J Med Plants Res 6(24):4087–4090

    Google Scholar 

Download references

Acknowledgements

This work is funded by in part by the Higher Education Commission of Pakistan under the HEC grant entitled: Identification and Characterization of genes Involved in Rheumatoid Arthritis from the Pakistani Population (Prj no: 20-1411/R&D/09). The authors would like to thank Dr. Irum Murtaza from the Department of Biochemistry and Molecular Biology, Quaid-e-Azam University, Islamabad, Pakistan for her valuable input and support for western blotting experimentation. We would like to thank Dr. Juan Dominguez-Bendala and Ms. Miriam Kathleen Gomez for their invaluable insight during manuscript preperation.  We would also like to thank Dr. Nasir Jalal, Mr Mubin Athar, Mr. Shahid Mehmood and Mr. Abdul Haseeb for their support. The authors would also like to thank the National Center for Physics, Islamabad, Pakistan for their help with GCMS. We are also thankful to Dr. Arshad and Mr. Inayat at the National Institute of Health, Islamabad, Pakistan, for their help in histopathological analysis.

Author information

Authors and Affiliations

  1. Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine, 1450 NW 10th Avenue, Miami, FL, 33136, USA

    Mirza Muhammad Fahd Qadir

  2. Department of Cell Biology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, 33136, USA

    Mirza Muhammad Fahd Qadir

  3. Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan

    Attya Bhatti, Muhammad Usman Ashraf, Sidrah Anjum & Peter John

  4. Department of Veterinary Basic Sciences, Faculty of Veterinary and Animal Sciences, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Rawalpindi, Pakistan

    Mansur Abdullah Sandhu

Authors
  1. Mirza Muhammad Fahd Qadir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Attya Bhatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muhammad Usman Ashraf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mansur Abdullah Sandhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sidrah Anjum
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter John
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M. M. F. Q. designed and performed all the experimentation, along with designed, wrote and revised the manuscript. He was also responsible for the development of the animal model outlined in this paper. A. B. supervised the project and provided insight into the design as well as manuscript preparation. M. U. A. assisted in the experimentation and manuscript preparation. M. A. S. provided insight into the experiment and provided the Griess reagent kit. S. A. assisted in the experimentation and manuscript preparation. P. J. provided valuable feedback regarding the experiment.

Corresponding author

Correspondence to Attya Bhatti.

Ethics declarations

Conflict of interest

The authors have no conflict of interests with any third party or persons.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qadir, M.M.F., Bhatti, A., Ashraf, M.U. et al. Immunomodulatory and therapeutic role of Cinnamomum verum extracts in collagen-induced arthritic BALB/c mice. Inflammopharmacol 26, 157–170 (2018). https://doi.org/10.1007/s10787-017-0349-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-017-0349-9

Keywords

Search

Navigation