Super-High-Dose Methylprednisolone Does Not Improve Efficacy or Induce Glucocorticoid Resistance in Experimental Allergic Encephalomyelitis

Wei, Zhisheng; Hong, Ming‐Fan; Quan-xi, SU; Wang, Xiaohui; Yu, Qingyun; Peng, Zhongxing; Zhang, Mingxing; Ao, Jie; Wang, Rui; Huang, Yeqing

doi:10.1159/000314736

Cited by 7 publications

(9 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In another study, MP had been therapeutically applied to Wistar rats in which EAE was induced by immunization with guinea pig spinal cord homogenate. In this case, MP also suppressed the disease which, however, could not be further potentiated by using dosages equivalent to the one we used here [23]. In contrast, if applied at lower doses, MP also exerted a dose-dependent effect in another rat EAE model [24].…”

Section: Discussionmentioning

confidence: 90%

Preventive Treatment with Methylprednisolone Paradoxically Exacerbates Experimental Autoimmune Encephalomyelitis

Wüst

Brandt

Reichardt

et al. 2012

International Journal of Endocrinology

View full text Add to dashboard Cite

Glucocorticoids (GCs) represent the standard treatment for acute disease bouts in multiple sclerosis (MS) patients, for which methylprednisolone (MP) pulse therapy is the most frequently used protocol. Here, we compared the efficacy of therapeutic and preventive MP application in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57Bl/6 mice. When administered briefly after the onset of the disease, MP efficiently ameliorated EAE in a dose-dependent manner. Surprisingly, MP administration around the time of immunization was contraindicated as it even increased leukocyte infiltration into the CNS and worsened the disease symptoms. Our analyses suggest that in the latter case an incomplete depletion of peripheral T cells by MP triggers homeostatic proliferation, which presumably results in an enhanced priming of autoreactive T cells and causes an aggravated disease course. Thus, the timing and selection of a particular GC derivative require careful consideration in MS therapy.

show abstract

Section: Discussionmentioning

confidence: 90%

Preventive Treatment with Methylprednisolone Paradoxically Exacerbates Experimental Autoimmune Encephalomyelitis

Wüst

Brandt

Reichardt

et al. 2012

International Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…During development, endogenous CS play an important role in CNS myelination (51,52) but repeated exogenous CS administration results in impaired brain development (53–55). These developmental effects must be clearly distinguished from the action of CS in the adult brain and during acute pathological and inflammatory events, such as in MS. Our in vitro results could be interpreted as a positive CS interference with the progression of the intrinsic differentiation programme, which leads to an acceleration of myelin marker gene expression in this cell culture system.…”

Section: Discussionmentioning

confidence: 99%

Corticosteroids Impair Remyelination in the Corpus Callosum of Cuprizone-Treated Mice

Clarner

Parabucki

Beyer

et al. 2011

Journal of Neuroendocrinology

View full text Add to dashboard Cite

Corticosteroids (CS) are effective in the treatment of many brain disorders, such as multiple sclerosis (MS) or traumatic brain injury. This has been scrutinised in different experimental animal models. However, neither the mechanisms, nor the site of CS action are fully understood. Short-term high-dose CS treatment improves MS symptoms and severity of clinical disability during an acute inflammatory exacerbation of disease. In the present study, we analysed the influence of CS on the expression of cellular and molecular markers of spontaneous endogenous remyelination in the toxic non-immune cuprizone animal model at early (9 days) and intermediate (21 days) remyelination, as well as steroidal effects in primary astrocytes and oligodendrocyte progenitor cultures. Dexamethasone (Dex) and methylprednisolone (MP) induced a higher expression of the differentiation markers myelin basic protein and proteolipid protein (PLP) in cultured oligodendrocyte progenitor cells (OPC). CS exposure of primary cultured astrocytes resulted in a greater expression of those genes involved in OPC proliferation [fibroblast growth factor 2 (FGF2) and platelet-derived growth factor (PDGF)-αα] and a reduced expression of the pro-maturation factor insulin-like growth factor 1. Pro-maturating effects of CS were completely blocked by FGF2 and PDGF-αα co-application in OPC cultures. MP treatment in vivo resulted in a reduced recovery of PLP-staining intensity, whereas the re-population of the demyelinated corpus callosum with adenomatous polyposis coli-expressing oligodendrocytes was not affected. The numbers of brain intrinsic inflammatory cells, microglia and astrocytes during remyelination were similar in placebo and MP-treated animals. Our findings suggest that treatment with CS might have, in addition to the well-known benefical effects on inflammatory processes, a negative influence on remyelination.

show abstract

“…In this sense, the MS and EAE-induced dysregulation of the HPA axis and neuroinflammation can be related to mood and cognitive symptoms 14,22 . Also, the treatment with synthetic GC could produce GR resistance through different mechanisms, such as (1) alternative splicing generating GRβ isoform in humans, (2) transactivation of others transcription factors, i.e., AP-1, and (3) modulation by non-classic kinases pathways, i.e., MAP kinases 23 . Furthermore, the augment of GC release by different types of stress can either protect 24 or potentialize 25 EAE progression.…”

Section: Introductionmentioning

confidence: 99%

High dose of dexamethasone protects against EAE-induced motor deficits but impairs learning/memory in C57BL/6 mice

Santos

Novaes

Dragunas

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Multiple sclerosis (MS) is an autoimmune and neuroinflammatory disease characterized by demyelination of the Central Nervous System. Immune cells activation and release of pro-inflammatory cytokines play a crucial role in the disease modulation, decisively contributing to the neurodegeneration observed in MS and the experimental autoimmune encephalomyelitis (EAE), the widely used MS animal model. Synthetic glucocorticoids, commonly used to treat the MS attacks, have controversial effects on neuroinflammation and cognition. We sought to verify the influence of dexamethasone (DEX) on the EAE progression and on EAE-induced cognitive deficits. In myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced EAE female mice, treated once with DEX (50 mg/kg) or not, on the day of immunization, DEX decreased EAE-induced motor clinical scores, infiltrating cells in the spinal cord and delayed serum corticosterone peak. At the asymptomatic phase (8-day post-immunization), DEX did not protected from the EAE-induced memory consolidation deficits, which were accompanied by increased glucocorticoid receptor (GR) activity and decreased EGR-1 expression in the hippocampus. Blunting hippocampal GR genomic activation with DnGR vectors prevented DEX effects on EAE-induced memory impairment. These data suggest that, although DEX improves clinical signs, it decreases cognitive and memory capacity by diminishing neuronal activity and potentiating some aspects of neuroinflammation in EAE.

show abstract

Super-High-Dose Methylprednisolone Does Not Improve Efficacy or Induce Glucocorticoid Resistance in Experimental Allergic Encephalomyelitis

Cited by 7 publications

References 62 publications

Preventive Treatment with Methylprednisolone Paradoxically Exacerbates Experimental Autoimmune Encephalomyelitis

Preventive Treatment with Methylprednisolone Paradoxically Exacerbates Experimental Autoimmune Encephalomyelitis

Corticosteroids Impair Remyelination in the Corpus Callosum of Cuprizone-Treated Mice

High dose of dexamethasone protects against EAE-induced motor deficits but impairs learning/memory in C57BL/6 mice

Contact Info

Product

Resources

About