Berberis vulgaris extract-based Fe3O4 nanocomposites affect NMDA1 function and physical activity: Analysis of Grin1 expression in Syrian mice model of Experimental autoimmune encephalomyelitis

Document Type : Original Article


Department of Biology, Faculty of Science and Engineering, Science and Arts University, Yazd, Iran.


Background: Ionotropic glutamate NMDA receptors are multi-subunit proteins with few selective pharmacological ligands and are tentatively implicated in MS and other neurodegenerative disorders. The present study was aimed at evaluating the antioxidant properties of Berberis vulgaris extract-loaded magnetite nanoparticles on the Grin1 gene expression in NMDA receptor in EAE Syrian mice.
Methods: EAE mice models were generated through active immunization with MBP and PTx and kept for days 9-14 until EAE signs appeared followed by administration of barberry extract loaded magnetic nanoparticles.
Results: Pure BE concentrations did not show recovery signs until days 7-9, but partial recovery in tail movement was seen on days 11 and 14, which was significant as compared to the control group in terms of improvement of the clinical scores. Meanwhile bare nanoparticles had neither disease recovery/progression properties nor EAE mice mortality as compared to controls, but 1 mg BE + Fe3O4 reduced EAE symptom severity and resulted in significant improvement of hind limb sensitivity to toe pinching and improved tail movements. Meanwhile 2 mg Be + Fe3O4 showed much better sensitivity to toe pinching and complete tail recovery. qRT-PCR analysis showed a significant decrease in relative Grin1 expression in female mice after treatment with 0.2 and 1 mg BE. However, a profound decrease in Grin1 expression was seen at 0.2, 1 and 2 mg BE + Fe3O4 treated groups in a dose-dependent manner.
Conclusion: The results indicated that Fe3O4+ BE could alleviate the EAE severity and progression 


1.Acobucci I, Wen J, Meggendorfer M. Genomic subtyping and therapeutic targeting of acute erythroleukemia. Nat Genet. 2019; 51: 694–704. 
2.Hasam-Henderson LA, Gotti GC, Mishto M. NMDA-receptor inhibition and oxidative stress during hippocampal maturation differentially alter parvalbumin expression and gamma-band activity. Sci Rep. 2018; 8: 9545. 
3.Franchini L, Stanic J, Ponzoni L. Linking NMDA receptor synaptic retention to synaptic plasticity and cognition. iScience 2019; 19: 927-939. 
4.Wyllie DJ, Livesey MR, Hardingham GE. Influence of GluN2 subunit identity on NMDA receptor function. Neuropharmacol. 2013; 74: 4–17. 
5.Wyllie DJA. Modelling the details: integrating structure with function. J Physiol. 2018; 596(17): 3833–3834. 
6.Malenka R. Intercellular communication in the nervous system. Saint Louis: Elsevier Science, 2014. 
7.Dwyer TM. Fundamental neuroscience for basic and clinical applications (Fifth Edition).  2018, Pages 54-71.e1. 
8.Lüscher C, Malenka RC. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect Biol. 2012; 4(6): a005710. 
9.Kim SY, Ahn BH, Kim J, Bae YS, Kwak JY, Min G, Kwon TK, Chang JS, Lee YH, Yoon SH, Min DS. Phospholipase C, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and redox state are involved in epigallocatechin gallate-induced phospholipase D activation in human astroglioma cells. Eur J Biochem. 2004; 271: 3470-80. 
10.Blanke ML, VanDongen AMJ. Activation mechanisms of the NMDA receptor. In: Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press/Taylor & Francis; 2009. Chapter 13. 
11.Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res. 2008; 22: 999–1012. 
12.Belwal T, Bisht A, Devkota HP, Ullah H, Khan H, Pandey A, Bhatt ID, Echeverría J. Phytopharmacology and clinical updates of Berberis species against diabetes and other metabolic diseases. Front Pharmacol. 11: 41. 
13.Rad SZK, Rameshrad M, Hosseinzadeh H. Toxicology effects of Berberis vulgaris (barberry) and its active constituent, berberine: a review. Iran J Basic Med Sci. 2017; 20(5): 516-529. 
14.Mirhadi E, Rezaee M, Malaekeh-Nikouei B. Nano strategies for berberine delivery, a natural alkaloid of Berberis. Biomed Pharmacotherapy, 2018; 104: 465–473. 
15.Dulińska-Litewka J, Łazarczyk A, Hałubiec P, Szafrański O, Karnas K, Karewicz A. Superparamagnetic iron oxide nanoparticles-current and prospective medical applications. Materials (Basel) 2019; 12: 617. 
16.Sankhalkar S, Vernekar V. Quantitative and qualitative analysis of phenolic and flavonoid content in Moringa oleifera Lam and Ocimum tenuiflorum L. Pharmacognosy Res. 2016; 8(1): 16-21.
17.Teng H, Choi O. Optimum extraction of bioactive alkaloid compounds from Rhizome coptidis (Coptis chinensis Franch.) using response surface methodology. Solvent Extr Res Dev 2013; 20: 91–104. 
18.Attarde D, Patil M, Chaudhari B, Pal S. Estimation of tannin content in some marketed Harde churna (Terminalia chebula Retz. Family Combretaceae). Int J Pharm Technol 2010; 2(3): 750-756.
19.Gulfraz M, Asad M, Qaddir G, Mehmood S, Shaukat S, Parveen Z. Phytochemical constituents of Berberis lycium royle and Justicia adhatoda. J Chem Soc Pak 2008; 30: 453-457.
20.Singleton VL, Orthofer R, Lamuela-Raventós RM. Analysis of total phenols and other oxidation substrates and antioxidants by means of folin-ciocalteu reagent Author links open overlay panel. Met Enzymol 1999; 299: 152–178.
21.Karimkhani MM, Salarbashi D, Sanjari Sefidy S, Mohammadzadeh A. Effect of extraction solvents on lipid peroxidation, antioxidant, antibacterial and antifungal activities of Berberis orthobotrys Bienerat ex CK Schneider. J Food Meas Charact 2019; 13: 357–367.
22.Abd El-Wahab AE, Ghareeb DA, Sarhan EE.  In vitro biological assessment of berberis vulgaris and its active constituent, berberine: antioxidants, anti-acetylcholinesterase, anti-diabetic and anticancer effects. BMC Complement Altern Med 2013; 13: 218.
23.Rufai Y. Comparative Phyto-constituents analysis from the root bark and root core extractives of cassia ferruginea (Schrad D. C) plant. Scholars J Agri Vet Sci 2016; 3: 275-283.
24.Javid A, Ahmadian S, Saboury AA, Kalantar SM, Rezaei-Zarchi S. Novel biodegradable heparin-coated nanocomposite system for targeted drug delivery. RSC Adv. 2014; 4: 13719-13728.
25.Costanza M. Type 2 inflammatory responses in autoimmune demyelination of the central nervous system: recent advances. J Immunol Res. 2019; 2019: 1-10. 
26.Bittner S, Afzali AM, Wiendl H, Meuth SG. Myelin oligodendrocyte glycoprotein (MOG35-55) induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. J Vis Exp 2014; 86: e51275. 
27.(Glatigny S and Bettelli E. Experimental autoimmune encephalomyelitis (EAE) as animal models of Multiple Sclerosis (MS). Cold Spring Harbor Perspectives in Medicine 2018; a028977.
28.Shahi SK, Freedman SN, Dahl RA. Scoring disease in an animal model of multiple sclerosis using a novel infrared-based automated activity-monitoring system. Sci Rep 2019; 9: 19194. 
29.Debiyi OO, Sofowora FA. Pytochemical screening of medical plants. Iloyidia. 1978; 3: 234–246. 
30.Ahlgren C, Odén A, Lycke J. High nationwide prevalence of multiple sclerosis in Sweden. Mult Scler. 2011; 17(8): 901-908. 
31.Wiedrick J, Meza-Romero R, Gerstner G, Seifert H, Chaudhary P, Headrick A, Kent G, Maestas A, Offner H. Sex differences in EAE reveal common and distinct cellular and molecular components. Cell Immunol 2021; 359: 104242.
32.Zarshenas MM, Ansari R, Dadbakhsh A Mohammadi M. A review of herbal remedies for Multiple Sclerosis-like disorders in Traditional Persian Medicine (TPM)”, Curr Drug Metabol 2018; 19(5): 392-407.
33.Wang Y, Liu Y, Du X, Ma H, Yao J. The anti-cancer mechanisms of berberine: A review. Cancer Manag Res. 2020; 12: 695-702.
34.Cardozo C, Inada A, Marcelino G, Figueiredo P, Arakaki D, Hiane P. Therapeutic potential of brazilian cerrado campomanesia species on metabolic dysfunctions. Mol. 2018; 23: 2336. 
35.Shirwaikar A, Shirwaikar A, Rajendran K, Punitha ISR. In vitro antioxidant studies on the benzyl tetra isoquinoline alkaloid berberine. Biol Pharm Bull. 2006; 29: 1906–1910. 
36.Rossi S, Studer V, Moscatelli A. Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis. PLoS One. 2013; 8(6): e67357.
37.Sharifi-Rad M, Lankatillake C, Dias DA, Docea AO, Mahomoodally MF, Lobine D, Chazot PL, Kurt B, Tumer TB, Moreira AC, Sharopov F, Martorell M, Martins N, Cho WC, Calina D and Sharifi-Rad J. Impact of natural compounds on neurodegenerative disorders: From preclinical to pharmacotherapeutics. J Clin Med 2020; 9: 1061-1079.
38.Ehteshamfar SM, Akhbari M, Afshari JT. Anti-inflammatory and immune-modulatory impacts of berberine on activation of autoreactive T cells in autoimmune inflammation. J Cell Mol Med 2020; 24(23): 13573-13588. 
39.Hooshmand Moghadam B, Kordi MR, Mahdian S. The effect of barberry juice supplement on prostaglandin E2 level caused by intense aerobic activity in active young girls. J Birjand Univ Med Sci. 2017; 24: 1-9.
40.Moradi SZ, Momtaz S, Bayrami Z, Farzaei MH, Abdollahi M. Nanoformulations of herbal extracts in treatment of neurodegenerative disorders. Front Bioeng Biotechnol. 2020; 8: 238.