Therapeutic Effect of Carvacrol-loaded Albumin Nanoparticles on Arthritic Rats

Document Type : Research article

Authors

1 Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

2 Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

3 Department of Immunology, School of Medical, Shiraz University of Medical Sciences, Shiraz, Iran.

4 Department of Chemistry, Payame Noor University, Shiraz, Iran.

Abstract

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Carvacrol,
an important natural terpenoid product in aromatic plants such as thyme, has shown antiinflammatory
effects in animal models of arthritis. However, its poor water solubility and
high volatility have limited its application. In the present study in order to overcome this
problem, we encapsulated carvacrol in the bovine serum albumin (BSA) nanoparticles and
examined its therapeutic and immunomodulatory effects in adjuvant-induced arthritis (AIA).
Carvacrol-loaded BSA nanoparticles were prepared by desolvation method. Nanoparticles
had encapsulation efficiency (EE) of 67.7 ± 6.9% and loading capacity (LC) of 26.6 ± 2%.
The size of particles was 148 ± 25 nm and they had monomodal distribution. After arthritis
induction, the rats were treated intraperitoneally with nanoparticle for every 3 days until day
28. The treatment of the rats with 375 mg/mL carvacrol-loaded BSA nanoparticle significantly
decreased clinical severity score (27.5 ± 9.8%, p = 0.008), erythrocyte sedimentation rate
(33.4 ± 10%, p = 0.02), nitric oxide production (82.3 ± 2.6%, p = 0.004) and interleukin (IL)-
17 gene expression (55.1 ± 8.2%, p = 0.003) compared to the untreated arthritic group. A
higher reduction in inflammation severity in arthritic rats treated with carvacrol-loaded BSA in
comparison to those treated with carvacrol alone was observed. In conclusion, encapsulation
of carvacrol in nanoparticles reduced arthritis signs and release of NO and IL-17 inflammatory
cytokine and therefore is suggested to be considered as a good approach for improving the
therapeutic applications of carvacrol in RA.

Graphical Abstract

Therapeutic Effect of Carvacrol-loaded Albumin Nanoparticles on Arthritic Rats

Keywords

Main Subjects


References
(1) Raychaudhuri S, Remmers EF, Lee AT, Hackett R,
Guiducci C, Burtt NP, Gianniny L, Korman BD,
Padyukov L, Kurreeman FA, Chang M and Catanese
JJ. Common variants at CD40 and other loci confer
risk of rheumatoid arthritis. Nat. Genet. (2008) 40:
1216-23.
(2) Goldring SR and Gravallese EM. Pathogenesis of
bone erosions in rheumatoid arthritis. Curr. Opin.
Rheumatol. (2000) 12: 195-9.
(3) Ainola MM, Mandelin JA, Liljeström MP, Li TF,
Hukkanen MV and Konttinen YT. Pannus invasion
and cartilage degradation in rheumatoid arthritis: 
319
Gholijani N et al. / IJPR (2020), 19 (1): 312-320
involvement of MMP-3 and interleukin-1b. Clin.
Exp. Rheumatol. (2005) 23: 644-50.
(4) Lubberts E and Berg WB. Cytokines in the
pathogenesis of rheumatoid arthritis and collageninduced arthritis. Madame Curie Bioscience
Database (2003) 2003: 194-202.
(5) Smolen JS, Redlich K, Zwerina J, Aletaha D, Steiner
G and Schett G. Pro-inflammatory cytokines in
rheumatoid arthritis. Clin. Rev. Allergy Immunol.
(2005) 28: 239-48.
(6) McInnes IB and Schett G. The pathogenesis of
rheumatoid arthritis. N. Engl. J. Med. (2011) 365:
2205-19.
(7) Miossec P, Korn T and Kuchroo VK. Interleukin-17
and type 17 helper T cells. N. Engl. J. Med. (2009)
361: 888-98.
(8) Paulissen SM, van Hamburg JP, Dankers W and
Lubberts E. The role and modulation of CCR6+
Th17 cell populations in rheumatoid arthritis.
Cytokine (2015) 74: 43-53.
(9) van Baarsen LG, Lebre MC, van der Coelen D,
Aarrass S, Tang MW, Ramwadhdoebe TH, Gerlag
DM and Tak PP. Heterogeneous expression pattern of
interleukin 17A (IL-17A), IL-17F and their receptors
in synovium of rheumatoid arthritis, psoriatic
arthritis and osteoarthritis: possible explanation for
nonresponse to anti-IL-17 therapy? Arthritis Res.
Ther. (2014) 16: 426.
(10) Bendele A. Animal models of rheumatoid arthritis.
J. Musculoskelet. Neuronal Interact. (2001) 1: 377-
85.
(11) Gholijani N, Gharagozloo M, Kalantar F, Ramezani
A and Amirghofran Z. Modulation of cytokine
production and transcription factors activities in
human jurkat t cells by thymol and carvacrol. Adv.
Pharm. Bull. (2015) 5: 653-60.
(12) Gholijani N, Gharagozloo M, Farjadian S and
Amirghofran Z. Modulatory effects of thymol and
carvacrol on inflammatory transcription factors
in lipopolysaccharide-treated macrophages. J.
Immunotoxicol. (2016) 13: 157-64.
(13) Liang D, Li F, Fu Y, Cao Y, Song X, Wang T, Wang
W, Guo M, Zhou E, Li D, Yang Z and Zhang N.
Thymol inhibits LPS-stimulated inflammatory
response via down-regulation of NF-κB and
MAPK signaling pathways in mouse mammary
epithelial cells. Inflammation (2014) 37: 214-22.
(14) Can Baser K. Biological and pharmacological
activities of carvacrol and carvacrol bearing
essential oils. Curr. Pharm. Des. (2008) 14: 3106-
19.
(15) Coimbra M, Isacchi B, van Bloois L, Torano JS,
Ket A, Wu X, Broere F, Metselaar JM, Rijcken CJ,
Storm G, Bilia R and Schiffelers RM. Improving
solubility and chemical stability of natural
compounds for medicinal use by incorporation into
liposomes. Int. J. Pharm. (2011) 416: 433-42.
(16) Kratz F, Fichtner I, Beyer U, Schumacher P, Roth T,
Fiebig HH and Unger C. 784-Antitumour activity
of acid labile transferrin and albumin doxorubicin
conjugates in in-vitro and in-vivo human tumour
xenograft models. Eur. J. Cancer (1997) 33: S175.
(17) Maryam K, Shakeri S and Kiani K. Preparation and
in-vitro investigation of antigastric cancer activities
of carvacrol-loaded human serum albumin
nanoparticles. IET Nanobiotechnol. (2015) 9: 294-
9.
(18) Marty J, Oppenheim R and Speiser P. Nanoparticles-
-a new colloidal drug delivery system. Pharm. Acta
Helv. (1978) 53: 17-23.
(19) Yu Z, Yu M, Zhang Z, Hong G and Xiong Q.
Bovine serum albumin nanoparticles as controlled
release carrier for local drug delivery to the inner
ear. Nanoscale Res. Lett. (2014) 9: 343.
(20) Kotronia M, Kavetsou E, Loupassaki S, Stefanos
Kikionis, Stamatina Vouyiouka and Anastasia
Detsi. Encapsulation of Oregano (Origanum
onites L.) essential oil in β-cyclodextrin (β-CD):
Synthesis and characterization of the inclusion
complexes. Bioengineering (Basel) (2017) 4: E74.
(21) Keawchaoon L and Yoksan R. Preparation,
characterization and in-vitro release study of
carvacrol-loaded chitosan nanoparticles. Colloids
Surf. B (2011) 84: 163-71.
(22) Ramadan G, Al-Kahtani MA and El-Sayed WM.
Anti-inflammatory and anti-oxidant properties
of Curcuma longa (turmeric) versus Zingiber
officinale (ginger) rhizomes in rat adjuvant-induced
arthritis. Inflammation (2011) 34: 291-301.
(23) Feng X and Jia A. Protective effect of carvacrol on
acute lung injury induced by lipopolysaccharide in
mice. Inflammation (2014) 37: 1091-101.
(24) Banji OJ, Banji D, Soumya N, Chilipi KK,
Kalpana CH, Kranthi Kumar CH and Annamalai
AR. Combination of carvacrol with methotrexate
suppresses Complete Freund’s adjuvant induced
synovial inflammation with reduced hepatotoxicity
in rats. Eur. J. Pharmacol. (2014) 723: 91-8.
(25) Tsikas D. Analysis of nitrite and nitrate in biological
fluids by assays based on the Griess reaction:
appraisal of the Griess reaction in the L-arginine/
nitric oxide area of research. J. Chromatogr. B
(2007) 851: 51-70.
(26) Thakur L, Ghodasra U, Patel N and Dabhi M.
Novel approaches for stability improvement in
natural medicines. Pharmacogn. Rev. (2011) 5: 48-
54.
(27) Chen Q, Liang C, Wang X, He J, Li Y and Liu Z. 
320
Carvacrol Nanoparticles Effect on Arthritic Rats
An albumin-based theranostic nano-agent for dualmodal imaging guided photothermal therapy to
inhibit lymphatic metastasis of cancer post surgery.
Biomaterials (2014) 35: 9355-62.
(28) Byeon HJ, Lee C, Lee S, Lee ES, Choi HG, Park
ES and Youn YS. Pharmaceutical potential of
tacrolimus-loaded albumin nanoparticles having
targetability to rheumatoid arthritis tissues. Int. J.
Pharm. (2016) 497: 268-76.
(29) Roberts CA, Dickinson AK and Taams LS. The
interplay between monocytes/macrophages and
CD4+ T cell subsets in rheumatoid arthritis. Front
Immunol. (2015) 6: 571.
(30) McInnes IBaGS. Cytokines in the pathogenesis of
rheumatoid arthritis. Nat. Rev. Immunol. (2007) 7:
429-42.
(31) Kugyelka R, Kohl Z, Olasz K, Mikecz K, Rauch
TA, Glant TT and Boldizsar F. Enigma of IL-17
and Th17 cells in rheumatoid arthritis and in
autoimmune animal models of arthritis. Mediat.
Inflamm. (2016) 2016: 1-11.
(32) Lubberts E. The IL-23-IL-17 axis in inflammatory
arthritis. Nat. Rev. Rheumatol. (2015) 11: 415-29.
(33) Al-Saadany HM, Hussein MS, Gaber RA and
Zaytoun HA. Th-17 cells and serum IL-17 in
rheumatoid arthritis patients: Correlation with
disease activity and severity. Egypt Rheumatol.
(2016) 38: 1-7.