Microglia Polarization by Methylprednizolone Acetate Accelerates Cuprizone Induced Demyelination

Overview

Journal J Mol Histol

Specialty Biochemistry

Date 2018 Aug 26

PMID 30143908

Citations 6

Authors

Golaleh Noorzehi

Parichehr Pasbakhsh

Maryam Borhani-Haghighi

Iraj Ragerdi Kashani

Soheila Madadi

Fatemeh Tahmasebi

Saied Nekoonam

Maryam Azizi

Affiliations

Soon will be listed here.

Abstract

Glucocorticoids (GC) are known as inflammatory drugs, which are used in neuroinflammatory diseases. Unlike the classic picture, recent studies have revealed that some GC drugs exacerbate inflammatory responses in their acute and prolonged administration. Multiple sclerosis (MS) is a demyelinating inflammatory disorder, in which reactive M1 microglia phenotype play a central role. Since methylprednisolone (MP), as a synthetic GC, are commonly used by MS patients, in this study, we evaluated the effect of long-term administration of MP on microglia polarization in cuprizone (CPZ)-induced MS model. The immunostaining results showed that chronic exposure to MP in the CPZ treated mice increased the number of Iba-1 positive microglia, which significantly expressed IP10 as M1 marker than arginase as M2 marker. MP treatment induced significant amplification in the transcript levels of iNOS and TNF-α (M1-related markers) in the corpus callosum of the MS mice, whereas no change detected in the expression of IL-10 (M2-related marker) between the groups. In addition, evaluation of myelin by luxol fast blue staining and transmission electron microscopy revealed that prolonged MP administration increased demyelination in comparison to the CPZ group. In conclusion, our results show that chronic MP therapy in the CPZ-induced demyelination model of MS polarized microglia to M1 pro-inflammatory phenotype.

Citing Articles

Microglia/macrophage polarization regulates spontaneous remyelination in intermittent cuprizone model of demyelination.

Zarini D, Pasbakhsh P, Mojaverrostami S, Amirizadeh S, Hashemi M, Shabani M Biochem Biophys Rep. 2024; 37:101630.

PMID: 38234370 PMC: 10793082. DOI: 10.1016/j.bbrep.2023.101630.

Forskolin, an Adenylcyclase/cAMP/CREB Signaling Activator Restoring Myelin-Associated Oligodendrocyte Destruction in Experimental Ethidium Bromide Model of Multiple Sclerosis.

Kapoor T, Mehan S, Suri M, Sharma N, Kumar N, Narula A Cells. 2022; 11(18).

PMID: 36139346 PMC: 9497421. DOI: 10.3390/cells11182771.

Medroxyprogesterone acetate attenuates demyelination, modulating microglia activation, in a cuprizone neurotoxic demyelinating mouse model.

Mohammadi M, Abdi M, Alidadi M, Mohamed W, Zibara K, Kashani I Am J Neurodegener Dis. 2021; 10(5):57-68.

PMID: 34824899 PMC: 8610806.

Cuprizone Affects Hypothermia-Induced Neuroprotection and Enhanced Neuroblast Differentiation in the Gerbil Hippocampus after Ischemia.

Kim W, Hahn K, Jung H, Kwon H, Nam S, Kim T Cells. 2020; 9(6).

PMID: 32531881 PMC: 7349804. DOI: 10.3390/cells9061438.

Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases.

De Nicola A, Meyer M, Guennoun R, Schumacher M, Hunt H, Belanoff J Int J Mol Sci. 2020; 21(6).

PMID: 32244957 PMC: 7139912. DOI: 10.3390/ijms21062137.

References

Clarner T, Parabucki A, Beyer C, Kipp M . Corticosteroids impair remyelination in the corpus callosum of cuprizone-treated mice. J Neuroendocrinol. 2011; 23(7):601-11. DOI: 10.1111/j.1365-2826.2011.02140.x. View

Sorrells S, Sapolsky R . An inflammatory review of glucocorticoid actions in the CNS. Brain Behav Immun. 2006; 21(3):259-72. PMC: 1997278. DOI: 10.1016/j.bbi.2006.11.006. View

Baxi E, DeBruin J, Tosi D, Grishkan I, Smith M, Kirby L . Transfer of myelin-reactive th17 cells impairs endogenous remyelination in the central nervous system of cuprizone-fed mice. J Neurosci. 2015; 35(22):8626-39. PMC: 4452559. DOI: 10.1523/JNEUROSCI.3817-14.2015. View

Aryanpour R, Pasbakhsh P, Zibara K, Namjoo Z, Boroujeni F, Shahbeigi S . Progesterone therapy induces an M1 to M2 switch in microglia phenotype and suppresses NLRP3 inflammasome in a cuprizone-induced demyelination mouse model. Int Immunopharmacol. 2017; 51:131-139. DOI: 10.1016/j.intimp.2017.08.007. View

Roy M, Sapolsky R . The exacerbation of hippocampal excitotoxicity by glucocorticoids is not mediated by apoptosis. Neuroendocrinology. 2003; 77(1):24-31. DOI: 10.1159/000068337. View

Torres R, Torres I, Laste G, Ferreira M, Guerreiro Cardoso P, Bello-Klein A . Effects of acute and chronic administration of methylprednisolone on oxidative stress in rat lungs. J Bras Pneumol. 2014; 40(3):238-43. PMC: 4109195. DOI: 10.1590/s1806-37132014000300006. View

Song G, Suk K . Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases. Front Aging Neurosci. 2017; 9:139. PMC: 5430023. DOI: 10.3389/fnagi.2017.00139. View

Borhani-Haghighi M, Kashani I, Mohamadi Y, Pasbakhsh P . Embryonic intraventricular transplantation of neural stem cells augments inflammation-induced prenatal brain injury. J Chem Neuroanat. 2018; 94:54-62. DOI: 10.1016/j.jchemneu.2018.06.003. View

Chen S, Zhang H, Pu H, Wang G, Li W, Leak R . n-3 PUFA supplementation benefits microglial responses to myelin pathology. Sci Rep. 2014; 4:7458. PMC: 4264015. DOI: 10.1038/srep07458. View

10.

Jha M, Lee W, Suk K . Functional polarization of neuroglia: Implications in neuroinflammation and neurological disorders. Biochem Pharmacol. 2015; 103:1-16. DOI: 10.1016/j.bcp.2015.11.003. View

11.

Kwon B, Fisher C, Dvorak M, Tetzlaff W . Strategies to promote neural repair and regeneration after spinal cord injury. Spine (Phila Pa 1976). 2005; 30(17 Suppl):S3-13. DOI: 10.1097/01.brs.0000175186.17923.87. View

12.

Graeber M, Streit W . Microglia: biology and pathology. Acta Neuropathol. 2009; 119(1):89-105. DOI: 10.1007/s00401-009-0622-0. View

13.

Subramaniam S, Federoff H . Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson's Disease. Front Aging Neurosci. 2017; 9:176. PMC: 5463358. DOI: 10.3389/fnagi.2017.00176. View

14.

MacPherson A, Dinkel K, Sapolsky R . Glucocorticoids worsen excitotoxin-induced expression of pro-inflammatory cytokines in hippocampal cultures. Exp Neurol. 2005; 194(2):376-83. DOI: 10.1016/j.expneurol.2005.02.021. View

15.

Dittrich A, Khouri C, Sackett S, Ehlting C, Bohmer O, Albrecht U . Glucocorticoids increase interleukin-6-dependent gene induction by interfering with the expression of the suppressor of cytokine signaling 3 feedback inhibitor. Hepatology. 2011; 55(1):256-66. DOI: 10.1002/hep.24655. View

16.

Montanaro D, Sanna V, Matarese G, Larby B, Racioppi L, Carrieri P . The fine specificity of human T cell lines towards myelin basic protein peptides in southern Italian multiple sclerosis patients. Clin Exp Immunol. 2001; 123(2):288-93. PMC: 1905994. DOI: 10.1046/j.1365-2249.2001.01457.x. View

17.

Sloka J, Stefanelli M . The mechanism of action of methylprednisolone in the treatment of multiple sclerosis. Mult Scler. 2005; 11(4):425-32. DOI: 10.1191/1352458505ms1190oa. View

18.

Nimmerjahn A, Kirchhoff F, Helmchen F . Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005; 308(5726):1314-8. DOI: 10.1126/science.1110647. View

19.

Holzknecht C, Rohl C . Effects of methylprednisolone and glatiramer acetate on nitric oxide formation of cytokine-stimulated cells from the rat oligodendroglial cell line OLN-93. Neuroimmunomodulation. 2009; 17(1):23-30. DOI: 10.1159/000243082. View

20.

Frank M, Hershman S, Weber M, Watkins L, Maier S . Chronic exposure to exogenous glucocorticoids primes microglia to pro-inflammatory stimuli and induces NLRP3 mRNA in the hippocampus. Psychoneuroendocrinology. 2014; 40:191-200. PMC: 3912460. DOI: 10.1016/j.psyneuen.2013.11.006. View