Steroid Protection in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis

Garay, Laura; Deniselle, Marı́a Claudia González; Gierman, Lobke; Meyer, Maria; Lima, Analı́a; Roig, Paulina; Nicola, Alejandro F. De

doi:10.1159/000135627

Cited by 72 publications

(69 citation statements)

References 88 publications

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“…Although it is well established that a subcutaneous injection of estrogen or ER agonist protects against neurodegenerative and CNS immune diseases (51)(52)(53), long-term use may increase the risk of breast cancer and cardiovascular disease (54). Conversely, the lentiviral manipulation of CNS ERα expression can mimic the therapeutic effect of estrogen, while avoiding unwanted side-effects.…”

Section: Discussionmentioning

confidence: 99%

Lentivirus-mediated estrogen receptor α overexpression in the central nervous system ameliorates experimental autoimmune encephalomyelitis in mice

Xiao

Qin

2013

International Journal of Molecular Medicine

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Abstract. Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory cell infiltration of the central nervous system (CNS) and multifocal demyelination. Clinical data and clinical indicators demonstrate that estrogen improves the relapse-remittance of MS patients. This study aimed to investigate the anti-inflammatory effects and the underlying mechanism(s) of action of estrogen and estrogen receptor α (ERα) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. An ERα recombinant lentivirus was constructed. Mouse neurons were cultured in serum-free culture medium, and ERα recombinant lentivirus with a multiplicity of infection (MOI) of 5 was used to infect the neurons. Furthermore, neuronal ERα mRNA and protein expression were detected using real-time quantitative PCR and western blot analysis. We sterotaxically injected ERα recombinant lentivirus into the lateral ventricle of mouse brains, and successfully identified infected neurons using Flag immunofluorescence staining to determine the optimal dose. A total of 75 C57BL/6 mice were ovariectomized. After 2 weeks, EAE was induced with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. The EAE mice were divided into 5 groups: the estrogen group (treatment with estradiol), the ERα agonist group (treatment with raloxifene), the ERα recombinant lentivirus group (ERα group, treatment with ERα recombinant lentivirus), the empty virus group and the normal saline (NS) group; clinical symptoms and body weight were compared among the groups. We assessed EAE-related parameters, detected pathological changes with immunohistochemistry and quantified the expression of myelin basic protein (MBP), matrix metalloproteinase-9 (MMP-9), and a subset of EAE-related cytokines using enzyme-linked immunosorbent assay (ELISA). We successfully constructed an ERα recombinant lentivirus. C57BL/6 mouse neurons can survive in culture for at least 8 weeks. During that period, the recombinant lentivirus was able to infect the neurons, while sustaining green fluorescence protein (GFP) expression. ERα recombinant lentivirus also infected the neurons at a MOI of 5. The ERα mRNA and protein expression levels were higher in the infected neurons compared to the uninfected ones. We successfully infected the CNS of C57BL/6 mice by stereotaxically injecting ERα recombinant lentivirus into the lateral ventricle of the mouse brains and induced EAE. The lentivirus-mediated overexpression of ERα reduced the incidence of EAE, ameliorated the clinical symptoms, inhibited inflammatory cell CNS infiltration, and reduced nerve fiber demyelination. MMP-9, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-17 and IL-23 expression levels were decreased, while those of MBP and IL-4 were increased. These data demonstrate that it is possible to induce the overexpression of ERα using a recombinant lentivirus, and that this novel intervention ameliorates EAE in a mouse model. Mechanistically, estrogen and ERα inhibit inflammatory responses, and ERα allev...

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Section: Discussionmentioning

confidence: 99%

Lentivirus-mediated estrogen receptor α overexpression in the central nervous system ameliorates experimental autoimmune encephalomyelitis in mice

Xiao

Qin

2013

International Journal of Molecular Medicine

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“…Recent studies resolve these discrepancies. Pretreatment with progesterone has been shown to decrease disease severity and reduce axonal damage and demyelination [82,83]. Yates et al [84] have examined the treatment potential of the hormone, administered after the induction of EAE.…”

Section: Influence Of Gender and Sex Hormones On Eaementioning

confidence: 99%

Sex Hormones and Multiple Sclerosis

Trenova¹

2016

Trending Topics in Multiple Sclerosis

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Experimental and clinical data about the influence of sex hormones on the course of multiple sclerosis (MS) grow rapidly during the past two decades. Estrogens, progesterone, and androgens have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in animals, and pregnancy in women is associated with a dramatic reduction in disease activity. Immunomodulatory and neuroprotective properties of sex hormones are the most probable underlying mechanisms, creating a background for testing similar hormonal treatments in humans. Several pilot studies in this field present promising results, but larger trials are necessary to identify the adverse events and to estimate precisely the place of sex steroids in multiple sclerosis therapeutic strategies.The objective of this chapter is to summarize the recent advances in the research about the effects of sex steroids in EAE and MS and to create a ground for the development of more powerful treatments in the future.

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“…[16][17][18] P4 treatment alone showed minor effects on EAE when used alone [19,20] and seemed to synergize with E2 to ameliorate EAE. [21] The potential protective effects of E4 on EAE have to our knowledge never been studied. In MS patients, a protective effect of estrogens has been reported in a pilot clinical trial using E3.…”

Section: The Protective Effects Of Pregnancy On Central Nervous Systementioning

confidence: 99%

Estrogen-mediated protection of experimental autoimmune encephalomyelitis: Lessons from the dissection of estrogen receptor-signaling in vivo

Laffont¹,

Garnier²,

Lélu³

et al. 2015

Biomed J

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A growing body of evidence from basic and clinical studies supports the therapeutic potential of estrogens in multiple sclerosis (MS), originating from the well-established reduction in relapse rates observed among women with MS during pregnancy. The biological effects of estrogens are mediated by estrogen receptors (ERα and ERβ). Estrogens or selective ER-agonists have been shown to exert potent neuroprotective or anti-inflammatory effects in experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. A central question in EAE is to identify the cellular targets that express a functional ER isotype, and the mechanisms underlying the neuroprotective and anti-inflammatory effects of estrogens. Using pharmacological approaches targeting ER-specific functions, and genetic tools such as conditional knockout mice in which ERα or ERβ are selectively deleted in specific cell populations, a clearer picture is now emerging of the various cellular targets and downstream molecules responsible for estrogen-mediated protection against central nervous system autoimmunity. (Biomed J 2015;38:194-205) Key words: experimental autoimmune encephalomyelitis, estrogen, estrogen receptors, immunoregulation, multiple sclerosis, neuroprotection M ultiple sclerosis (MS) is a debilitating neurological autoimmune disease (AID) affecting 2.5 million people worldwide, with a female/male sex ratio of 3:1. MS and its mouse model, experimental autoimmune encephalomyelitis (EAE), are characterized by the infiltration of inflammatory leukocytes, including autoreactive T-cells, into the central nervous system (CNS), resulting in myelin damage. A large body of evidence from basic science and from preclinical and clinical studies points to anti-inflammatory and direct neuroprotective effects of estrogens in MS.[1] The concept that estrogens may play a role in MS pathogenesis and disease activity, and, therefore, constitute potential for therapeutic agents, is based on the well-established clinical observation that women with MS constantly show a decrease in disease activity during pregnancy.[2] This potent, short-term beneficial effect of pregnancy is not limited to women with MS, but also has been observed in other inflammatory AID, such as rheumatoid arthritis (RA) and psoriasis, followed by a temporary rebound of disease activity postpartum. [3,4] Estrogens are the major candidate therapeutic agents in MS since they exert potent effects on the immune system and on the CNS, and peak during the last trimester of pregnancy, when the most pronounced decrease in the relapse rate occurs. Indeed, the therapeutic potential of estrogens, such as 17β-estradiol (E2) or estriol (E3), has been clearly demonstrated in EAE. [4,5] Moreover, in a pilot clinical trial of MS therapy, administration of estriol (E3) at doses related to pregnancy levels of the hormone was shown to exert beneficial effects. [6,7] Large placebo-controlled clinical trials of estrogen therapy in MS are in progress. [4] Although, clear evidence are emerging that E2 could inh...

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Steroid Protection in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis

Cited by 72 publications

References 88 publications

Lentivirus-mediated estrogen receptor α overexpression in the central nervous system ameliorates experimental autoimmune encephalomyelitis in mice

Lentivirus-mediated estrogen receptor α overexpression in the central nervous system ameliorates experimental autoimmune encephalomyelitis in mice

Sex Hormones and Multiple Sclerosis

Estrogen-mediated protection of experimental autoimmune encephalomyelitis: Lessons from the dissection of estrogen receptor-signaling in vivo

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