Synthesis and evaluation of the effects of solid lipid nanoparticles of ivermectin and ivermectin on cuprizone-induced demyelination via targeting the TRPA1/NF-kB/GFAP signaling pathway

Document Type : Original Article

Authors

1 Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

2 Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

3 Experimental medicine research center, Tehran University of medical sciences, Tehran, Iran

4 Student Research Committee, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran

5 Research Group on Community Nutrition and Oxidative Stress (NUCOX) and Health Research Institute of Balearic Islands (IdISBa), University of Balearic Islands-IUNICS, Palma de Mallorca E-07122, Balearic Islands, Spain

6 CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid

Abstract

Objective(s): Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) and its cause is unknown. Several environmental and genetic factors may have roles in the pathogenesis of MS. The synthesis of solid lipid nanoparticles (SLNs) for ivermectin (IVM) loading was performed to increase its efficiency and bioavailability and evaluate its ability in improving the behavioral and histopathological changes induced by cuprizone (CPZ) in the male C57BL/6 mice.   
Materials and Methods: Four groups of 7 adult C57BL/6 mice including control (normal diet), CPZ, IVM, and nano-IVM groups were chosen. After synthesis of nano-ivermectin, demyelination was induced by adding 0.2% CPZ to animal feed for 6 weeks. IVM and nano-IVM (1 mg/kg/day, IP) were given for the final 14 days of the study. At last, behavioral tests, histochemical assays, and immunohistochemistry of TRPA1, NF-kB p65, and GFAP were done.
Results: The time of immobility of mice in the IVM and nano-IVM groups was reduced compared to the CPZ group. Histopathological examination revealed demyelination in the CPZ group, which was ameliorated by IVM and nano-IVM administration. In IVM and nano-IVM groups corpus callosum levels of TRPA1, NF-kB p65, and GFAP were decreased compared to the CPZ group. In the IVM and nano-IVM groups, the levels of MBP were significantly higher than in the CPZ group. 
Conclusion: The results evidenced that IVM and nano-IVM administration is capable of reducing demyelination in mice.

Keywords

Main Subjects

References

1.    Khaledi E, Noori T, Mohammadi-Farani A, Sureda A, Dehpour AR, Yousefi-Manesh H, et al. Trifluoperazine reduces cuprizone-induced demyelination via targeting Nrf2 and IKB in mice. Eur J Pharmacol 2021;909:174432.
2.    Noori T, Dehpour AR, Sureda A, Fakhri S, Sobarzo-Sanchez E, Farzaei MH, et al. The role of glycogen synthase kinase 3 beta in multiple sclerosis. Biomed Pharmacother 2020;132:110874.
3.    Weber MS, Hemmer B. Cooperation of B cells and T cells in the pathogenesis of multiple sclerosis. Results Probl Cell Differ 2010:115-126.
4.    Van Langelaar J, Rijvers L, Smolders J, van Luijn MM. B and T cells driving multiple sclerosis: Identity, mechanisms and potential triggers. Front Immunol 2020;11:1-12.
5.    Wang P, Xie K, Wang C, Bi J. Oxidative stress induced by lipid peroxidation is related with inflammation of demyelination and neurodegeneration in multiple sclerosis. Eur Neurol 2014;72:249-254.
6.    Trentini A, Castellazzi M, Romani A, Squerzanti M, Baldi E, Caniatti ML, et al. Evaluation of total, ceruloplasmin-associated and type II ferroxidase activities in serum and cerebrospinal fluid of multiple sclerosis patients. J Neurol Sci 2017;377:133-136.
7.    Zhang SY, Gui LN, Liu YY, Shi S, Cheng Y. Oxidative stress marker aberrations in multiple sclerosis: A meta-analysis study. Front Neurosci 2020;14:1-8.
8.    Vega-Riquer JM, Mendez-Victoriano G, Morales-Luckie RA, Gonzalez-Perez O. Five decades of cuprizone, an updated model to replicate demyelinating diseases. Curr Neuropharmacol 2019;17:129-141.
9.    Manto M. Abnormal Copper Homeostasis: Mechanisms and Roles in Neurodegeneration. Toxics 2014;2:327-345.
10. Skripuletz T, Bussmann JH, Gudi V, Koutsoudaki PN, Pul R, Moharregh-Khiabani D, et al. Cerebellar cortical demyelination in the murine cuprizone model. Brain Pathol 2010;20:301-312.
11. Silverman HA, Chen A, Kravatz NL, Chavan SS, Chang EH. Involvement of neural transient receptor potential channels in peripheral inflammation. Front Immunol 2020; 11:1-18.
12. Moran MM, Xu H, Clapham DE. TRP ion channels in the nervous system. Current opinion in neurobiology. 2004;14:362-369.
13. Wang YY, Chang RB, Waters HN, McKemy DD, Liman ER. The nociceptor ion channel TRPA1 is potentiated and inactivated by permeating calcium ions. J Biol Chem 2008;283:32691-32703.
14. Shang S, Zhu F, Liu B, Chai Z, Wu Q, Hu M, et al. Intracellular TRPA1 mediates Ca2+ release from lysosomes in dorsal root ganglion neurons. J Cell Biol 2016;215:369-381.
15. Kheradpezhouh E, Choy JMC, Daria VR, Arabzadeh E. TRPA1 expression and its functional activation in rodent cortex. Open Biol 2017;7:1-12
16. Mihai DP, Nitulescu GM, Ion GND, Ciotu CI, Chirita C, Negres S. Computational Drug Repurposing Algorithm Targeting TRPA1 Calcium Channel as a Potential Therapeutic Solution for Multiple Sclerosis. Pharmaceutics 2019;11:1-24.
17. Oh S-J, Lee JM, Kim H-B, Lee J, Han S, Bae JY, et al. Ultrasonic neuromodulation via astrocytic TRPA1. Curr Biol 2019;29:3386-3401. e8.
18. Shigetomi E, Jackson-Weaver O, Huckstepp RT, O’Dell TJ, Khakh BS. TRPA1 channels are regulators of astrocyte basal calcium levels and long-term potentiation via constitutive D-serine release. J Neurosci Res 2013;33:10143-10153.
19. Shigetomi E, Tong X, Kwan KY, Corey DP, Khakh BS. TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nat Neurosci 2012;15:70-80.
20. Landini L, Souza Monteiro de Araujo D, Titiz M, Geppetti P, Nassini R, De Logu F. TRPA1 Role in Inflammatory Disorders: What Is Known So Far? Int J Mol Sci 2022;23:4529.
21. Sághy É, Sipos É, Ács P, Bölcskei K, Pohóczky K, Kemény Á, et al. TRPA1 deficiency is protective in cuprizone-induced demyelination-A new target against oligodendrocyte apoptosis. Glia 2016;64:2166-2180.
22. Mihai DP, Nitulescu GM, Ion GND, Ciotu CI, Chirita C, Negres S. Computational drug repurposing algorithm targeting TRPA1 calcium channel as a potential therapeutic solution for multiple sclerosis. Pharmaceutics 2019;11:446.
23. Nuzzo D, Picone P. Multiple Sclerosis: Focus on Extracellular and Artificial Vesicles, Nanoparticles as Potential Therapeutic Approaches. Int J Mol Sci 2021;22:1-12.
24. Laing R, Gillan V, Devaney E. Ivermectin–old drug, new tricks? Trends Parasitol 2017;33:463-472.
25. Stein L, Kircik L, Fowler J, Tan J, Draelos Z, Fleischer A, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol 2014;13:316-323.
26. Taieb A, Ortonne J, Ruzicka T, Roszkiewicz J, Berth‐Jones J, Peirone M, et al. Superiority of ivermectin 1% cream over metronidazole 0· 75% cream in treating inflammatory lesions of rosacea: a randomized, investigator‐blinded trial. BJD 2015;172:1103-1110.
27. Chen IS, Kubo Y. Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin. J Physiol 2018;596:1833-1845.
28. Lu M, Xiong D, Sun W, Yu T, Hu Z, Ding J, et al. Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: In vitro and in vivo evaluation. Drug Deliv  2017;24:622-631.
29. Pandita D, Kumar S, Poonia N, Lather V. Solid lipid nanoparticles enhance oral bioavailability of resveratrol, a natural polyphenol. Food Res Int 2014;62:1165-1174.
30. Madan JR, Khude PA, Dua K. Development and evaluation of solid lipid nanoparticles of mometasone furoate for topical delivery. Int J Pharm Investig 2014;4:60-64.
31. Ghasemiyeh P, Mohammadi-Samani S. Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: Applications, advantages and disadvantages. Res Pharm Sci 2018;13:288-303.
32. Chauhan H, Mohapatra S, Munt DJ, Chandratre S, Dash A. Physical-chemical characterization and formulation considerations for solid lipid nanoparticles. AAPS PharmSciTech 2016;17:640-651.
33. Bennewitz MF, Saltzman WM. Nanotechnology for delivery of drugs to the brain for epilepsy. Neurotherapeutics 2009;6:323-336.
34. Wissing SA, Kayser O, Müller RH. Solid lipid nanoparticles for parenteral drug delivery. Adv Drug Deliv Rev 2004;56:1257-1272.
35. Ahmadifard Z, Ahmeda A, Rasekhian M, Moradi S, Arkan E. Chitosan-coated magnetic solid lipid nanoparticles for controlled release of letrozole. J Drug Deliv Sci Technol 2020;57:101621.
36. Maher A, Radwan R, Breitinger H-G. In vivo protection against strychnine toxicity in mice by the glycine receptor agonist ivermectin. Biomed Res Int 2014;2014:1-9.
37. Dalenogare DP, Theisen MC, Peres DS, Fialho MFP, Lückemeyer DD, Antoniazzi CTdD, et al. TRPA1 activation mediates nociception behaviors in a mouse model of relapsing-remitting experimental autoimmune encephalomyelitis. Exp Neurol 2020;328:113241.
38. Dehpour AR, Khaledi E, Noori T, Mohammadi-Farani A, Delphi L, Sureda A, et al. Dapsone reduced cuprizone-induced demyelination via targeting Nrf2 and IKB in C57BL/6 mice. Iran J Basic Med Sci 2022;25:675-682.
39. Loeser JD, Treede RD. The Kyoto protocol of IASP basic pain Terminology. Pain 2008;137:473-447.
40. Ruan Y, Gu L, Yan J, Guo J, Geng X, Shi H, et al. An effective and concise device for detecting cold allodynia in mice. Sci Rep 2018;8:1-7.
41. Shirooie S, Esmaeili J, Sureda A, Esmaeili N, Mirzaee Saffari P, Yousefi-Manesh H, et al. Evaluation of the effects of metformin administration on morphine tolerance in mice. Neurosci Lett 2020;716:134638.
42. Weickenmeier J, de Rooij R, Budday S, Ovaert TC, Kuhl E. The mechanical importance of myelination in the central nervous system. J Mech Behav Biomed Mater 2017;76:119-124.
43. Ma S, Chen F, Ye X, Dong Y, Xue Y, Xu H, et al. Intravenous microemulsion of docetaxel containing an anti-tumor synergistic ingredient (Brucea javanica oil): Formulation and pharmacokinetics. Int J Nanomedicine 2013;8:4045-52.
44. Ojha S, Kumar B. Preparation and statistical modeling of solid lipid nanoparticles of dimethyl fumarate for better management of multiple sclerosis. Adv Pharm Bull 2018;8:225-233.
45. Guo D, Dou D, Li X, Zhang Q, Bhutto ZA, Wang L. Ivermection-loaded solid lipid nanoparticles: preparation, characterisation, stability and transdermal behaviour. Artif Cells Nanomed Biotechnol 2018;46:255-262.
46. Ghanbarzadeh S, Hariri R, Kouhsoltani M, Shokri J, Javadzadeh Y, Hamishehkar H. Enhanced stability and dermal delivery of hydroquinone using solid lipid nanoparticles. Colloids Surf B 2015;136:1004-1010.
47. Mulik RS, Mönkkönen J, Juvonen RO, Mahadik KR, Paradkar AR. Transferrin mediated solid lipid nanoparticles containing curcumin: Enhanced in vitro anticancer activity by induction of apoptosis. Int J Pharm 2010;398:190-203.
48.    Torkildsen Ø, Brunborg L, Myhr KM, Bø L. The cuprizone model for demyelination. Acta Neurol Scand 2008;117:72-76.
49.    Elbaz EM, Senousy MA, El-Tanbouly DM, Sayed RH. Neuroprotective effect of linagliptin against cuprizone-induced demyelination and behavioural dysfunction in mice: a pivotal role of AMPK/SIRT1 and JAK2/STAT3/NF-κB signalling pathway modulation. Toxicol Appl Pharmacol 2018;352:153-161.
50.    Ye J-N, Chen X-S, Su L, Liu Y-L, Cai Q-Y, Zhan X-L, et al. Progesterone alleviates neural behavioral deficits and demyelination with reduced degeneration of oligodendroglial cells in cuprizone-induced mice. PLoS One 2013;8:e54590.
51. Zhan J, Mann T, Joost S, Behrangi N, Frank M, Kipp M. The cuprizone model: Dos and do nots. Cells 2020;9:1-21.
52. Li Y, Yang J, Zhang Y, Meng Q, Bender A, Chen X. Computational drug repositioning for ischemic stroke: neuroprotective drug discovery. Future Med Chem 2021;13:1271-1283.
53. Estrada-Mondragon A, Lynch JW. Functional characterization of ivermectin binding sites in α1β2γ2L GABA (A) receptors. Front Mol Neurosci 2015;8:1-13.
54. Nörenberg W, Sobottka H, Hempel C, Plötz T, Fischer W, Schmalzing G, et al. Positive allosteric modulation by ivermectin of human but not murine P2X7 receptors. Br J Pharmacol 2012;167:48-66.
55. Cairns DM, Giordano JE, Conte S, Levin M, Kaplan DL. Ivermectin promotes peripheral nerve regeneration during wound healing. ACS Omega 2018;3:12392-12402.
56. Blackiston DJ, Anderson GM, Rahman N, Bieck C, Levin M. A novel method for inducing nerve growth via modulation of host resting potential: gap junction-mediated and serotonergic signaling mechanisms. Neurotherapeutics 2015;12:170-184. 
57. Andries M, Van Damme P, Robberecht W, Van Den Bosch L. Ivermectin inhibits AMPA receptor-mediated excitotoxicity in cultured motor neurons and extends the life span of a transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2007;25:8-16.
58. Deber CM, Reynolds SJ. Central nervous system myelin: structure, function, and pathology. Clin Biochem. 1991;24:113-134.
59. Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 2003;349:139-145.
60. Namer IJ, Steibel J, Poulet P, Armspach JP, Mohr M, Mauss Y, et al. Blood—brain barrier breakdown in MBP-specific T cell induced experimental allergic encephalomyelitis: A quantitative in vivo MRI study. Brain 1993;116:147-159.
61. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal transduction and targeted therapy. Signal Transduct Target Ther 2017;2:1-9.
62. Gilmore TD. Introduction to NF-kappaB: Players, pathways, perspectives. Oncogene 2006;25:6680-6684.
63. Bacher S, Schmitz ML. The NF-kB pathway as a potential target for autoimmune disease therapy. Curr Pharm Des 2004;10:2827-2837.
64. Gupta SC, Sundaram C, Reuter S, Aggarwal BB. Inhibiting NF-κB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta 2010;1799:775-787.
65. Nunes AKS, Rapôso C, Rocha SWS, de Sousa Barbosa KP, de Almeida Luna RL, da Cruz-Hoefling MA, et al. Involvement of AMPK, IKβα-NFκB and eNOS in the sildenafil anti-inflammatory mechanism in a demyelination model. Brain Res 2015;1627:119-133.
66. Portmann-Baracco A, Bryce-Alberti M, Accinelli RA. Antiviral and anti-inflammatory properties of ivermectin and its potential use in Covid-19. Arch Bronconeumol 2020;56:831-836.
67. Zhang X, Song Y, Ci X, An N, Ju Y, Li H, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res 2008;57:524-529.
68. Ritter C, Dalenogare DP, de Almeida AS, Pereira VL, Pereira GC, Fialho MFP, et al. Nociception in a Progressive Multiple Sclerosis Model in Mice Is Dependent on Spinal TRPA1 Channel Activation. Molecular neurobiology. 2020;57:2420-2435.
69. Sághy É, Sipos É, Ács P, Bölcskei K, Pohóczky K, Kemény Á, et al. TRPA1 deficiency is protective in cuprizone‐induced demyelination—A new target against oligodendrocyte apoptosis. Glia. 2016;64:2166-2180.
70. Wang XL, Cui LW, Liu Z, Gao YM, Wang S, Li H, et al. Effects of TRPA1 activation and inhibition on TRPA1 and CGRP expression in dorsal root ganglion neurons. Neural Regen Res 2019;14:140-148.
71. Lee KI, Lee HT, Lin HC, Tsay HJ, Tsai FC, Shyue SK, et al. Role of transient receptor potential ankyrin 1 channels in Alzheimer’s disease. J Neuroinflammation 2016;13:1-16.
72. Hamilton NB, Kolodziejczyk K, Kougioumtzidou E, Attwell D. Proton-gated Ca2+-permeable TRP channels damage myelin in conditions mimicking ischaemia. Nature 2016;529:523-527.
73. Ko HK, Lin AH, Perng DW, Lee TS, Kou YR. Lung epithelial TRPA1 mediates lipopolysaccharide-induced lung inflammation in bronchial epithelial cells and mice. Front Physiol 2020:11:1-11.
74. Yuan J, Liang X, Zhou W, Feng J, Wang Z, Shen S, et al. TRPA1 promotes cisplatin-induced nephrotoxicity through inflammation mediated by the MAPK/NF-κB signaling pathway. Ann Transl Med 2021;9:1-13.
75. Luostarinen S, Hämäläinen M, Moilanen E. Transient receptor potential ankyrin 1 (TRPA1)—an inflammation-induced factor in human HaCaT keratinocytes. Int J Mol Sci 2021;22:1-12.
76. Samways DS, Khakh BS, Egan TM. Allosteric modulation of Ca2+ flux in ligand-gated cation channel (P2X4) by actions on lateral portals. JBC 2012;287:7594-7602.
77. von Boyen GB, Schulte N, Pflüger C, Spaniol U, Hartmann C, Steinkamp M. Distribution of enteric glia and GDNF during gut inflammation. BMC Gastroenterol 2011;11:1-7.
78.    Kassubek R, Gorges M, Schocke M, Hagenston VAM, Huss A, Ludolph AC, et al. GFAP in early multiple sclerosis: A biomarker for inflammation. Neurosci Lett 2017;657:166-170.
79. Takano R, Misu T, Takahashi T, Sato S, Fujihara K, Itoyama Y. Astrocytic damage is far more severe than demyelination in NMO: A clinical CSF biomarker study. Neurology 2010;75:208-216.
80. Smith ME, Eng LF. Glial fibrillary acidic protein in chronic relapsing experimental allergic encephalomyelitis in SJL/J mice. J Neurosci Res 1987;18:203-208.
81. Luo J, Ho P, Steinman L, Wyss-Coray T. Bioluminescence in vivo imaging of autoimmune encephalomyelitis predicts disease. J Neuroinflammation 2008;5:1-6.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 11
November 2023
Pages 1272-1282

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