Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of anti-inflammatory response of berberine-loaded gum nanocomplexes in carrageenan-induced acute paw edema in rats

  • Article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

Berberine is a natural plant alkaloid and has been reported to possess anti-inflammatory activity. However, berberine’s poor bioavailability and low solubility have limited its clinical applicability. Nanoencapsulation of berberine using a suitable carrier can be a promising strategy to improve its efficacy. Therefore, this study aimed to produce berberine-loaded gum nanocomplexes to evaluate their therapeutic effects in a carrageenan-induced rat model.

Methods

Berberine-loaded gum nanocomplexes were prepared by the ionic complexation between the negative charges of the gums (tragacanth and acacia gum) using a cross-linker for loading cationic berberine and their anti-inflammatory activity was evaluated against carrageenan-induced paw edema in rats. ELISA and qRT-PCR were employed to measure the concentration and mRNA expression level of inflammatory mediators in plasma and paw tissue, respectively.

Results

Berberine nanocomplexes were characterized for particle size (219.5 nm), zeta potential by the dynamic light scattering (DLS), and for entrapment efficiency (93.2%) Infrared spectroscopy affirmed the loading of berberine in gum nanocomplexes. Transmission electron microscopy of formulation showed the spherical shape of nanocomplexes and small particle size (100–150 nm). Pretreatment of rats with berberine nanocomplexes significantly reduced the paw edema in inflamed rat paws, decreased the production of nitrite and TNF-α in plasma and repressed the mRNA expression levels of TNF-α and IL-1β in paw tissue in comparison to berberine per se treated rats.

Conclusion

The obtained berberine-loaded gum nanocomplexes produced a better anti-inflammatory effect as compared to berberine alone and hence can be used as an efficient candidate in the treatment of inflammation.

Graphical abstract

The schematic representation of the preparation of the preparation of berberine-loaded tragacanth/acacia gum nanocomplexes and the evaluation in vivo for anti-inflammatory effects.

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

Data availability

Raw data of study are the accessible. The authors will provide appropriate data on a suitable request.

Abbreviations

ANOVA:

Analysis of variance

cDNA:

Complementary DNA

COX-2:

Cyclooxygenase-2

DLS:

Dynamic light scattering

ELISA:

Enzyme-linked immunosorbent assay

FT-IR:

Fourier-transform infrared spectroscopy

IAEC:

Institutional Animal Ethics Committee

IL-1β:

Interleukin-1β

iNOS:

Inducible nitrite oxide synthase

NO:

Nitric oxide

PDI:

Polydispersity index

qRT-PCR:

Quantitative real-time polymerase chain reaction

TEM:

Transmission electron microscope

TNF-α:

Tumor necrosis factor-α

References

  1. Gyurkovska V, Alipieva K, Maciuk A, Dimitrova P, Ivanovska N, Haas C, et al. Anti-inflammatory activity of Devil’s claw in vitro systems and their active constituents. Food Chem. 2011;125:171–8.

    Article  CAS  Google Scholar 

  2. Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. Int J Mol Sci. 2019;20:e6008.

    Article  PubMed  Google Scholar 

  3. Osadebe PO, Okoye FBC. Anti-inflammatory effects of crude methanolic extract and fractions of Alchornea cordifolia leaves. J Ethnopharmacol. 2003;89:19–24.

    Article  CAS  PubMed  Google Scholar 

  4. Kim TH, Kang MS, Mandakhbayar N, El-Fiqi A, Kim HW. Anti-inflammatory actions of folate functionalized bioactive ion-releasing nanoparticles imply drug-free nanotherapy of inflamed tissues. Biomaterials. 2019;207:23–38.

    Article  CAS  PubMed  Google Scholar 

  5. Zuo F, Nakamura N, Akao T, Hattori M. Pharmacokinetics of berberine and its main metabolites in conventional and pseudo germ-free rats determined by liquid chromatography/ion trap mass spectrometry. Drug Metab Dispos. 2006;34:2064–72.

    Article  CAS  PubMed  Google Scholar 

  6. Xue M, Yang MX, Zhang W, Li XM, Gao DH, Ou ZM, et al. Characterization, pharmacokinetics, and hypoglycemic effect of solid lipid nanoparticles. Int J Nanomed. 2013;8:4677–87.

    Article  Google Scholar 

  7. Kuo CL, Chi CW, Liu TY. The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett. 2004;203:127–37.

    Article  CAS  PubMed  Google Scholar 

  8. Kupeli E, Kosar M, Yesilada E, Husnu K, Baser C. A comparative study on the anti-inflammatory, antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species. Life Sci. 2002;72:645–57.

    Article  CAS  PubMed  Google Scholar 

  9. Wang SD, Song BS, Li K. Determination of berberine in decocted liquid from shenshu granules with water by reversed-phase liquid chromatography. Se Pu. 2000;18:261–2.

    CAS  PubMed  Google Scholar 

  10. Sahibzada MUK, Sadiq A, Faidah HS, Khurram M, Amin MU, Haseeb A, et al. Berberine nanoparticles with enhanced in vitro bioavailability: characterization and antimicrobial activity. Drug Des Dev Ther. 2018;12:303–12.

    Article  CAS  Google Scholar 

  11. Saleh SR, Abady MM, Nofal M, Yassa NW, Abdel-Latif MS, Nounou MI, et al. Berberine nanoencapsulation attenuates hallmarks of scoplomine induced Alzheimer’s-like disease in rats. Curr Rev Clin Exp Pharmacol. 2021;16:139–54.

    PubMed  Google Scholar 

  12. Patel P. A bird’s eye view on therapeutically ‘wonder molecule’: berberine. Phytomedicine Plus. 2021;1(3):e100070.

    Article  Google Scholar 

  13. Wang Y, Wen B, Yu H, Ding D, Zhang J, Zhang Y, et al. Berberine hydrochloride-loaded chitosan nanoparticles effectively targets and suppresses human nasopharyngeal carcinoma. J Biomed Nanotechnol. 2018;14:1486–95.

    Article  CAS  PubMed  Google Scholar 

  14. Jin J, Xu M, Liu Y, Ji Z, Dai K, Zhang L, et al. Alginate-based composite microspheres coated by berberine simultaneously improves hemostatic and antibacterial efficacy. Colloids Surf B. 2020;194:e111168.

    Article  Google Scholar 

  15. Lin YH, Lin JH, Chou SC, Chang SJ, Chung CC, Chen YS, et al. Berberine-loaded targeted nanoparticles as specific Helicobacter pylori eradication therapy: in vitro and in vivo study. Nanomedicine. 2015;10:57–71.

    Article  PubMed  Google Scholar 

  16. Khemani M, Sharon M, Sharon M. Encapsulation of berberine in nano sized PLGA synthesized by emulsification method. ISRN Nanotechnol. 2012;1–9:e187354.

    Google Scholar 

  17. Al-Awady MJ, Fauchet A, Greenway GM, Paunov VN. Enhanced antimicrobial effect of berberine in nanogel carriers with cationic surface functionality. J Mater Chem B. 2017;38:7885–97.

    Article  Google Scholar 

  18. Stoyanova N, Ignatova M, Manolova N, Rashkov I, Toshkova R, Georgieva A. Nanoparticles based on complex of berberine chloride and polymethacrylic or polyacrylic acid with antioxidant and in vitro antitumor activities. Int J Pharm. 2020;584:e119426.

    Article  Google Scholar 

  19. Dash S, Kumar M, Pareek N. Enhanced antibacterial potential of berberine via synergism with chitosan nanoparticles. Mater Today Proc. 2020;31:e506.

    Google Scholar 

  20. Wang L, Li H, Wang S, Liu R, Wu Z, Wang C, et al. Enhancing the antitumor activity of berberine hydrochloride by solid lipid nanoparticle encapsulation. AAPS PharmSci Tech. 2014;15:834–44.

    Article  CAS  Google Scholar 

  21. Zhang Y, Liu H. Development of bioadhesive microspheres for oral bioavailability enhancement of berberine hydrochloride. Int J Polym Sci. 2016;2016:1–7. https://doi.org/10.1155/2016/4235832

    Article  CAS  Google Scholar 

  22. Taheri A, Jafari SM. Gum-based nanocarriers for the protection and delivery of food bioactive compounds. Adv Colloid Interface Sci. 2019;269:277–95.

    Article  CAS  PubMed  Google Scholar 

  23. Vojdani A, Vojdani C. Immune reactivities against gums. Altern Ther Health Med. 2015;21:64–72.

    PubMed  Google Scholar 

  24. Cikrikci S, Mert B, Oztop MH. Development of pH sensitive alginate/gum tragacanth based hydrogels for oral insulin delivery. J Agric Food Chem. 2018;66:11784–96.

    Article  CAS  PubMed  Google Scholar 

  25. Ghayempour S, Montazer M, Rad MM. Encapsulation of Aloe Vera extract into natural Tragacanth Gum as a novel green wound healing product. Int J Biol Macromol. 2016;93:344–9.

    Article  CAS  PubMed  Google Scholar 

  26. Singh B, Sharma K, Dutt S, Rajneesh. Dietary fibre tragacanth gum based hydrogels for use in drug delivery applications. Dietary fibre tragacanth. Bioact Carbohydr Diet Fibre. 2020;21:e100208.

    Article  Google Scholar 

  27. Kashmir observer. Health benefits of Tragacanth gum (Kateer). https://kashmirobserver.net/. Accessed 21 May 2019.

  28. Sheorain J, Mehra M, Thakur R, Grewal S, Kumari S. In vitro anti-inflammatory and antioxidant potential of thymol loaded bipolymeric (tragacanth gum/chitosan) nanocarrier. Int J Biol Macromol. 2019;125:1069–74.

    Article  CAS  PubMed  Google Scholar 

  29. Gupta VK, Sood S, Agarwal S, Saini AK, Pathania D. Antioxidant activity and controlled drug delivery potential of tragacanth gum-cl-poly (lactic acid-co-itaconic acid) hydrogel. Int J Biol Macromol. 2018;107:2534–43.

    Article  CAS  PubMed  Google Scholar 

  30. Lamsen MRL, Wang T, D’Souza D, Dia V, Chen G, Zhong Q. Encapsulation of vitamin D3 in gum arabic to enhance bioavailability and stability for beverage applications. J Food Sci. 2020;85:2368–79.

    Article  CAS  PubMed  Google Scholar 

  31. Ali BH, Al-Husseni I, Beegam S, Al-Shukaili A, Nemmar A, Schierling S, et al. Effect of gum Arabic on oxidative stress and inflammation in adenine-induced chronic renal failure in rats. PLoS One. 2013;8:e55242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hassani A, Mahmood S, Enezei HH, Hussain SA, Hamad HA, Aldoghachi AF, et al. Formulation, characterization and biological activity screening of sodium alginate-gum Arabic nanoparticles loaded with curcumin. Molecules. 2020;25:e2244.

    Article  PubMed  Google Scholar 

  33. Tan C, Xie J, Zhang X, Cai J, Xia S. Polysaccharide-based nanoparticles by chitosan and gum arabic polyelectrolyte complexation as carriers for curcumin. Food Hydrocoll. 2016;57:236–45.

    Article  CAS  Google Scholar 

  34. Oliveira JL, Campos EVR, Pereira AES, Nunes LES, Silva CCL, Pasquoto T, et al. Geraniol encapsulated in chitosan/gum Arabic nanoparticles: a promising system for pest management in sustainable agriculture. J Agric Food Chem. 2018;66:5325–34.

    Article  PubMed  Google Scholar 

  35. Jhundoo HD, Siefen T, Liang A, Schmidt C, Lokhnauth J, Moulari B, et al. Anti-inflammatory effects of acacia and guar gum in 5-amino salicylic acid formulations in experimental colitis. Int J Pharm X. 2021;3:e100080.

    Google Scholar 

  36. Singh B, Rajneesh. Gamma radiation synthesis and characterization of gentamicin loaded polysaccharide gum based hydrogel wound dressings. J Drug Deliv Sci Technol. 2018;47:200–8.

    Article  CAS  Google Scholar 

  37. Bernela M, Ahuja M, Thakur R. Enhancement of anti-inflammatory activity of glycyrrhizic acid by encapsulation in chitosan-katira gum nanoparticles. Eur J Pharm Biopharm. 2016;105:141–7.

    Article  CAS  PubMed  Google Scholar 

  38. Chen HB, Luo CD, Liang JL, Zhang ZB, Lin GS, Wu JZ, et al. Anti-inflammatory activity of coptisine free base in mice through inhibition of NF-kappaB and MAPK signaling pathways. Eur J Pharmacol. 2017;811:222–31.

    Article  CAS  PubMed  Google Scholar 

  39. Hussein SZ, Yusoff KM, Makpol S, Yusof YAM. Gelam honey inhibits the production of proinflammatory, mediators NO, PGE2, TNF-α, and IL-6 in carrageenan-induced acute paw edema in rats. Evid Based Complement Altern Med. 2012;2012:1–13. https://doi.org/10.1155/2012/109636.

    Article  Google Scholar 

  40. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem. 1982;126:131–8.

    Article  CAS  PubMed  Google Scholar 

  41. Rio DC, Ares M Jr, Hannon GJ, Nilsen TW. Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb Protoc. 2010;6:e5439.

    Article  Google Scholar 

  42. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real time quantitative PCR and the 2(-Delta DeltaC(T)) method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  43. Hennink WE, Nostrum CF. Novel crosslinking methods to design hydrogels. Adv Drug Deliv Rev. 2002;54:13–36.

    Article  CAS  PubMed  Google Scholar 

  44. Surini S, Azzahrah FU, Ramadon D. Microencapsulation of Grape seed oil (Vitis Vinifera L.) with gum Arabic as a coating polymer by crosslinking emulsification method. Int J Appl Pharm. 2018;10:194–8.

    Article  CAS  Google Scholar 

  45. Kiani A, Shahbazi M, Asempour H. Hydrogel membranes based on gum tragacanth with tunable structures and properties. II. Comprehensive characterization of the swelling behavior. J Appl Polym Sci. 2012;124:99–108.

    Article  CAS  Google Scholar 

  46. Fernandes AV, Pydi CR, Verma R, Jose J, Kumar L. Design, preparation and in vitro characterizations of fluconazole loaded nanostructured lipid carriers. Braz J Pharm Sci. 2020;56:e18069.

    Article  CAS  Google Scholar 

  47. Chopra M, Bernela M, Kaur P, Manuja A, Kumar B, Thakur R. Alginate/gum acacia bipolymeric nanohydrogels—promising carrier for zinc oxide nanoparticles. Int J Biol Macromol. 2015;72:827–33.

    Article  CAS  PubMed  Google Scholar 

  48. Minkal, Ahuja M, Bhatt DC. Carboxylmethy gum katira: synthesis, characterization and evaluation for nanoparticulate drug delivery. RSC Adv. 2015;5:82363–73.

    Article  CAS  Google Scholar 

  49. Dilbaghi N, Kaur H, Ahuja M, Kumar S. Preparation and evaluation of enrofloxacin-loaded solid lipid nanoparticles. J Nanoeng Nanomanuf. 2013;3:147–53.

    Article  CAS  Google Scholar 

  50. Battu SK, Repka MA, Maddineni S, Chittiboyina AG, Avery MA, Majumdar S. Physicochemical characterization of berberine chloride: a perspective in the development of a solution dosage form for oral delivery. AAPS Pharm Sci Tech. 2010;11:1466–75.

    Article  CAS  Google Scholar 

  51. Kurt A. Physicochemical, rheological and structural characteristics of alcohol precipitated fraction of gum tragacanth. Food Health. 2018;4:183–93.

    Article  Google Scholar 

  52. Patel PK, SS P. Preparation and characterization of crosslinked gum acacia microspheres by single step emulsion in-situ polymer crosslinking method: a potential vehicle for controlled drug delivery. Res Rev J Pharm Pharm Sci. 2013;2:40–8.

    Google Scholar 

  53. Kundu P, Das M, Tripathy K, Sahoo SK. Delivery of dual drug loaded lipid based nanoparticles across the blood-brain barrier impart enhanced neuroprotection in a rotenone induced mouse model of Parkinson’s disease. ACS Chem Neurosci. 2016;7:1658–70.

    Article  CAS  PubMed  Google Scholar 

  54. Wang X, Feng S, Ding N, He Y, Li C, Li M, et al. Anti-inflammatory effects of berberine hydrochloride in an LPS-induced murine model of mastitis. Evid Based Complement Altern Med. 2018;2018:1–9. https://doi.org/10.1155/2018/5164314.

    Article  Google Scholar 

  55. Zeeshan M, Ali H, Khan S, Khan SA, Weigmann B. Advances in orally-delivered pH-sensitive nanocarrier systems; an optimistic approach for the treatment of inflammatory bowel disease. Int J Pharm. 2019;558:201–14.

    Article  CAS  PubMed  Google Scholar 

  56. Mansouri MT, Hemmati AA, Naghizadeh B, Mard SA, Rezaie A, Ghorbanzadeh B. A study of the mechanisms underlying the anti-inflammatory effect of ellagic acid in carrageenan-induced paw edema in rats. Indian J Pharmacol. 2015;47:292–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sengar N, Joshi A, Prasad SK, Hemalatha S. Anti-inflammatory, analgesic and antipyretic activities of standardized root extract of Jasminum sambac. J Ethnopharmacol. 2015;160:140–8.

    Article  PubMed  Google Scholar 

  58. Cheng J, Ma T, Liu W, Wang H, Jiang J, Wei Y, et al. In in vivo evaluation of the anti-inflammatory and analgesic activities of compound Muniziqi granule in experimental animal models. BMC Complement Altern Med. 2016;16:20.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Posadas I, Bucci M, Roviezzo F, Rossi A, Parente L, Sautebin L, et al. Carrageenan-induced mouse paw oedema is biphasic, age-weight dependent and displays differential nitric oxide cyclooxygenase-2 expression. Br J Pharmacol. 2004;142:331–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lee SA, Moon SM, Choi YH, Han SH, Park BR, Choi MS, et al. Aqueous extract of Codium fragile suppressed inflammatory responses in lipopolysaccharide-stimulated RAW264.7 cells and carrageenan-induced rats. Biomed Pharmacother. 2017;93:1055–64.

    Article  CAS  PubMed  Google Scholar 

  61. Orlikova B, Schumacher M, Juncker T, Yan CC, Inayat-Hussain SH, Hajjouli S, et al. Styryl-lactone goniothalamin inhibits TNF-α-induced NF-κB activation. Food Chem Toxicol. 2013;59:572–8.

    Article  CAS  PubMed  Google Scholar 

  62. Halici Z, Dengiz GO, Odabasoglu F, Suleyman H, Cadirci E, Halici M. Amiodarone has anti-inflammatory and antioxidative properties: an experimental study in rats with carrageenan-induced paw edema. Eur J Pharmacol. 2007;566:215–21.

    Article  CAS  PubMed  Google Scholar 

  63. Zhang H, Shang C, Tian Z, Amin HK, Kassab RB, Moneim AEA, et al. Diallyl disulfide suppresses inflammatory and oxidative machineries following carrageenan injection-induced paw edema in mice. Mediat Inflamm. 2020;202:e8508906.

    Google Scholar 

  64. Tan L, Wang Y, Ai G, Luo C, Chen H, Li C, et al. Dihydroberberine, a hydrogenated derivative of berberine firstly identified in Phellodendri Chinese Cortex, exerts anti-inflammatory effect via dual modulation of NF-κB and MAPK signaling pathways. Int Immunopharmacol. 2019;75:e105802.

    Article  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the Department of Bio and Nano Technology; and Experimental Animal Facility, Guru Jambheshwar University Science and Technology (Hisar), Sophisticated Analytical Instrumentation Facility (SAIF), AIIMS, New Delhi for providing the facilities for carrying out this research work.

Funding

This research was funded by Guru Jambheshwar University Science and Technology, Hisar (Haryana, India).

Author information

Authors and Affiliations

  1. Department of Bio and Nano Technology, Guru Jambheshwar University of Science and Technology, Hisar, India

    Jyoti Bakshi, Meenakshi Mehra, Sapna Grewal & Santosh Kumari

  2. Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar, India

    Prity Lathar & Dinesh Dhingra

Authors
  1. Jyoti Bakshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prity Lathar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meenakshi Mehra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sapna Grewal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dinesh Dhingra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Santosh Kumari
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: SK; performed the literature search and data analysis: JB; drafted and revised the work: JB, SK, DD. All the authors read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Santosh Kumari.

Ethics declarations

Conflict of interest

The author declares that there are no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 63 kb)

Supplementary file2 (XLSX 37 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bakshi, J., Lathar, P., Mehra, M. et al. Evaluation of anti-inflammatory response of berberine-loaded gum nanocomplexes in carrageenan-induced acute paw edema in rats. Pharmacol. Rep 74, 392–405 (2022). https://doi.org/10.1007/s43440-021-00350-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43440-021-00350-z

Keywords

Search

Navigation