scholarly journals A Novel Zinc Chelator, 1H10, Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating Zinc Toxicity and AMPK Activation

2020 ◽  
Vol 21 (9) ◽  
pp. 3375
Author(s):  
Bo Young Choi ◽  
Jeong Hyun Jeong ◽  
Jae-Won Eom ◽  
Jae-Young Koh ◽  
Yang-Hee Kim ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Term Treatment ◽  
Histological Evaluation ◽  
Zinc Toxicity ◽  
Autoimmune Encephalomyelitis ◽  
Long Term Treatment ◽  
Zinc Chelation ◽  
Experimental Autoimmune

Previous studies in our lab revealed that chemical zinc chelation or zinc transporter 3 (ZnT3) gene deletion suppresses the clinical features and neuropathological changes associated with experimental autoimmune encephalomyelitis (EAE). In addition, although protective functions are well documented for AMP-activated protein kinase (AMPK), paradoxically, disease-promoting effects have also been demonstrated for this enzyme. Recent studies have demonstrated that AMPK contributes to zinc-induced neurotoxicity and that 1H10, an inhibitor of AMPK, reduces zinc-induced neuronal death and protects against oxidative stress, excitotoxicity, and apoptosis. Here, we sought to evaluate the therapeutic efficacy of 1H10 against myelin oligodendrocyte glycoprotein 35-55-induced EAE. 1H10 (5 μg/kg) was intraperitoneally injected once per day for the entire experimental course. Histological evaluation was performed three weeks after the initial immunization. We found that 1H10 profoundly reduced the severity of the induced EAE and that there was a remarkable suppression of demyelination, microglial activation, and immune cell infiltration. 1H10 also remarkably inhibited EAE-associated blood-brain barrier (BBB) disruption, MMP-9 activation, and aberrant synaptic zinc patch formation. Furthermore, the present study showed that long-term treatment with 1H10 also reduced the clinical course of EAE. Therefore, the present study suggests that zinc chelation and AMPK inhibition with 1H10 may have great therapeutic potential for the treatment of multiple sclerosis.

Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis

2011 ◽  
Vol 17 (8) ◽  
pp. 939-948 ◽  
Author(s):  
Sarah Al-Izki ◽  
Gareth Pryce ◽  
Samuel J Jackson ◽  
Gavin Giovannoni ◽  
David Baker
Keyword(s):  
Early Intervention ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immunosuppressive Agents ◽  
Term Treatment ◽  
Autoimmune Encephalomyelitis ◽  
Treatment Benefit ◽  
Secondary Progressive ◽  
Receptor Modulator ◽  
Long Term Treatment ◽  
Experimental Autoimmune

Background: There has been poor translation for the use of immunosuppressive agents from experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), into the treatment of MS. This may be due to the fact that most EAE studies examine prophylactic, pre-treatment regimes that prove to be therapeutically-ineffective in long-established, often progressive, MS. FTY720 (fingolimod/Gilenya) is a sphingosine-1-phosphate receptor modulator. This is a new oral agent that markedly reduces the number of relapses in people with MS, compared with currently licensed injectable agents such as the beta interferons. FTY720 has activity against lymphocytes but may also influence oligodendroglia and could therefore have the potential to influence progressive MS, by promoting remyelination. Methods: The effect of FTY720 was assessed in relapsing-progressive EAE in mice. Results: Early intervention during relapsing EAE could completely inhibit subsequent relapses, inhibited the accumulation of neurodegeneration, and facilitated motor recovery. However, when examined in secondary progressive EAE, that develops after the accumulation of deficit from relapsing disease, long-term treatment with FTY720 failed to slow deterioration when initiated late (4 months) into the disease course. Conclusions: This study indicates that early intervention with immunosuppressive agents may inhibit the generation of the neurodegenerative microenvironment, which is no longer responsive to potent immunosuppression. However, if treatment is initiated too late, progressive, neurological-disease continues unabated. This suggests that immunosuppression is insufficient to control secondary progression in animals, as has been found so far to be the case in MS, and may warrant early intervention with FTY720 for optimal treatment benefit.

scholarly journals Selenization of S. cerevisiae increases its protective potential in experimental autoimmune encephalomyelitis by triggering an intestinal immunomodulatory loop

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Thais Fernanda de Campos Fraga-Silva ◽  
Luiza Ayumi Nishiyama Mimura ◽  
Larissa Ragozo Cardoso de Oliveira ◽  
Juliana Helena dos Santos Toledo ◽  
Patrícia Aparecida Borim ◽  
...  
Keyword(s):  
Immune Response ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Lymph Nodes ◽  
Therapeutic Potential ◽  
Clinical Signs ◽  
Mesenteric Lymph Nodes ◽  
Autoimmune Encephalomyelitis ◽  
Complementary Medicines ◽  
Mesenteric Lymph ◽  
Experimental Autoimmune

AbstractMultiple sclerosis is an autoimmune disease that affects the myelinated central nervous system (CNS) neurons and triggers physical and cognitive disabilities. Conventional therapy is based on disease-modifying drugs that control disease severity but can also be deleterious. Complementary medicines have been adopted and evidence indicates that yeast supplements can improve symptoms mainly by modulating the immune response. In this investigation, we evaluated the therapeutic potential of Saccharomyces cerevisiae and its selenized derivative (Selemax) in experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice submitted to EAE induction were orally supplemented with these yeasts by gavage from day 0 to day 14 after EAE induction. Both supplements determined significant reduction in clinical signs concomitantly with diminished Th1 immune response in CNS, increased proportion of Foxp3+ lymphocytes in inguinal and mesenteric lymph nodes and increased microbiota diversity. However, Selemax was more effective clinically and immunologically; it reduced disease prevalence more sharply, increased the proportion of CD103+ dendritic cells expressing high levels of PD-L1 in mesenteric lymph nodes and reduced the intestinal inflammatory process more strongly than S. cerevisiae. These results suggest a clear gut-brain axis modulation by selenized S. cerevisiae and suggest their inclusion in clinical trials.

scholarly journals Nogo-Receptor 1 Deficiency Has No Influence on Immune Cell Repertoire or Function during Experimental Autoimmune Encephalomyelitis

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e82101 ◽  
Author(s):  
Sara A. Litwak ◽  
Natalie L. Payne ◽  
Naomi Campanale ◽  
Ezgi Ozturk ◽  
Jae Young Lee ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cell ◽  
Cell Repertoire ◽  
Autoimmune Encephalomyelitis ◽  
Nogo Receptor ◽  
Experimental Autoimmune

scholarly journals A Mushroom Extract Piwep fromPhellinus igniariusAmeliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Immune Cell Infiltration in the Spinal Cord

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Lan Li ◽  
Guang Wu ◽  
Bo Young Choi ◽  
Bong Geom Jang ◽  
Jin Hee Kim ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Lymph Node ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Immune Cell Infiltration ◽  
Autoimmune Encephalomyelitis ◽  
Phellinus Igniarius ◽  
Mushroom Extract ◽  
Experimental Autoimmune

The present study aimed to evaluate the therapeutic potential of a mushroom extract fromPhellinus igniariusin an animal model of multiple sclerosis. The medicinal mushroom,Phellinus igniarius, contains biologically active compounds that modulate the human immune system. Experimental autoimmune encephalomyelitis (EAE) was induced by immunization with myelin oligodendrocyte glycoprotein (MOG 35–55) in C57BL/6 female mice. A water-ethanol extract ofPhellinus igniarius(Piwep) was delivered intraperitoneally every other day for the entire experimental course. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were examined. Piwep injection profoundly decreased the daily incidence rate and clinical score of EAE. The Piwep-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, macrophages, and B cells in the spinal cord. Piwep reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in the spinal cord and integrin-α4in the lymph node of EAE mice. Piwep also inhibited proliferation of lymphocytes and secretion of interferon-γin the lymph node of EAE mice. The results suggest that a mushroom extract, Piwep, may have a high therapeutic potential for ameliorating multiple sclerosis progression.

scholarly journals Inhibition of lysophosphatidic acid receptor 1-3 deteriorates experimental autoimmune encephalomyelitis by inducing oxidative stress

2020 ◽  
Author(s):  
Jong Hee Choi ◽  
Jinhee Oh ◽  
Min Jung Lee ◽  
Ik-Hyun Cho
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Lysophosphatidic Acid ◽  
Cell Activation ◽  
Immune Cell ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Demyelinating Diseases ◽  
Autoimmune Encephalomyelitis ◽  
Therapeutic Implications ◽  
Ifn Γ ◽  
Experimental Autoimmune

Abstract Background Lysophosphatidic acid receptors (LPARs) are G-protein-coupled receptors involved in many physiological functions in the central nervous system. However, the role of the LPARs in multiple sclerosis (MS) has not been clearly defined yet. Methods Here, we investigated the roles of LPARs in myelin oligodendrocyte glycoprotein peptides-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Results Pre-inhibition with antagonists ameliorated behavioral symptoms of EAElo. Specifically, LPAR1-3 antagonist Ki16425 (intraperitoneal) deteriorated symptoms of EAElow associated with increased demyelination, chemokine expression, cellular infiltration, and immune cell activation (microglia and macrophage) in spinal cords of mice compared to the sham group. This LPAR1-3 antagonist also increased the infiltration of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells into spinal cords of EAElow mice along with upregulated mRNA expression of IFN-γ and IL-17 and impaired BBB in the spinal cord. The underlying mechanism for negative effects of LPAR1-3 antagonist was associated with the overproduction of reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) 2 and NOX3. Interestingly, LPAR1/2 agonist 1-oleoyl-LPA (LPA 18:1) (intraperitoneal) ameliorated symptoms of EAEhigh and improved representative pathological features of spinal cords of EAEhigh mice. Conclusions Our findings strongly suggest that some agents that can stimulate LPARs might have potential therapeutic implications for autoimmune demyelinating diseases such as MS.

Sign in / Sign up

Export Citation Format

Share Document