Investigating Extended Linker Analogues of Risperidone for Treatment of Multiple Sclerosis

10.26686/wgtn.17147636 ◽

2021 ◽

Author(s):

◽

Thomas Bird

Keyword(s):

Multiple Sclerosis ◽

Cytokine Production ◽

Chronic Inflammatory Disease ◽

Immunomodulatory Effects ◽

Structure Activity ◽

Neurotropic Drugs ◽

New Treatments ◽

Insight Into ◽

Reduce Disease Severity

<p>Risperidone is a second-generation antipsychotic used to treat psychiatric disorders such as schizophrenia, bipolar disorder and autism. It targets dopamine D2 and serotonin 5-HT2A receptors and has immunomodulatory properties. Multiple sclerosis is a chronic inflammatory disease that affects over 2 million people worldwide and currently has no cure. Recent research at Victoria University of Wellington has shown that risperidone is able to reduce disease severity in mouse models of multiple sclerosis. Further research has demonstrated that truncated and unsaturated analogues of risperidone have varying immunomodulatory effects in immune cells. The current research describes the synthesis and preliminary in vitro testing of four extended-linker analogues of risperidone. Structure-activity relationship studies with neurotropic drugs have shown that altering the length of the alkyl chain found in many of these compounds can have significant effects on receptor binding profiles. Synthesis and cytokine production assays of these analogues begin to provide further insight into how risperidone exerts its immunomodulatory effects and may contribute to the development of new treatments for multiple sclerosis.</p>

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CRYAB modulates the activation of CD4+ T cells from relapsing–remitting multiple sclerosis patients

Multiple Sclerosis Journal ◽

10.1177/1352458513489853 ◽

2013 ◽

Vol 19 (14) ◽

pp. 1867-1877 ◽

Cited By ~ 10

Author(s):

Que Lan Quach ◽

Luanne M Metz ◽

Jenna C Thomas ◽

Jonathan B Rothbard ◽

Lawrence Steinman ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Cytokine Production ◽

Clinical Signs ◽

Healthy Controls ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Multiple Sclerosis Patients ◽

Relapsing Remitting Multiple Sclerosis

Background: Suppression of activation of pathogenic CD4+ T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS. Objective: We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease. Methods: CD4+ T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73–92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated. Results: The secretion of pro-inflammatory cytokines by CD4+ T cells was decreased in the presence of CRYAB in a subset of relapsing–remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Further, there was a correlation for higher levels of miR181a microRNA, a marker upregulated in tolerant CD8+ T cells, in CD4+ T cells of MS patients that displayed suppressed cytokine production (responders). Conclusion: CRYAB may be capable of suppressing the activation of CD4+ T cells from a subset of RRMS patients who appear to have less disability but similar age and disease duration.

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Vitamin D/CD46 Crosstalk in Human T Cells in Multiple Sclerosis

Frontiers in Immunology ◽

10.3389/fimmu.2020.598727 ◽

2020 ◽

Vol 11 ◽

Author(s):

Justin Killick ◽

Joanne Hay ◽

Elena Morandi ◽

Sonja Vermeren ◽

Saniya Kari ◽

...

Keyword(s):

Multiple Sclerosis ◽

Vitamin D ◽

T Cells ◽

T Cell ◽

Chronic Inflammatory Disease ◽

Vitamin D Supplementation ◽

Type I ◽

T Cell Migration ◽

The Impact

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which T-cell migration into the CNS is key for pathogenesis. Patients with MS exhibit impaired regulatory T cell populations, and both Foxp3+ Tregs and type I regulatory T cells (Tr1) are dysfunctional. MS is a multifactorial disease and vitamin D deficiency is associated with disease. Herein, we examined the impact of 1,25(OH)2D3 on CD4+ T cells coactivated by either CD28 to induce polyclonal activation or by the complement regulator CD46 to promote Tr1 differentiation. Addition of 1,25(OH)2D3 led to a differential expression of adhesion molecules on CD28- and CD46-costimulated T cells isolated from both healthy donors or from patients with MS. 1,25(OH)2D3 favored Tr1 motility though a Vitamin D-CD46 crosstalk highlighted by increased VDR expression as well as increased CYP24A1 and miR-9 in CD46-costimulated T cells. Furthermore, analysis of CD46 expression on T cells from a cohort of patients with MS supplemented by vitamin D showed a negative correlation with the levels of circulating vitamin D. Moreover, t-Distributed Stochastic Neighbor Embedding (t-SNE) analysis allowed the visualization and identification of clusters increased by vitamin D supplementation, but not by placebo, that exhibited similar adhesion phenotype to what was observed in vitro. Overall, our data show a crosstalk between vitamin D and CD46 that allows a preferential effect of Vitamin D on Tr1 cells, providing novel key insights into the role of an important modifiable environmental factor in MS.

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Structure-Activity Relationship of (1.RAR.3)-.BETA.-D-Glucans in the Induction of Cytokine Production from Macrophages, in Vitro.

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.18.1320 ◽

1995 ◽

Vol 18 (10) ◽

pp. 1320-1327 ◽

Cited By ~ 98

Author(s):

Mitsuhiro OKAZAKI ◽

Yoshiyuki ADACHI ◽

Naohito OHNO ◽

Toshiro YADOMAE

Keyword(s):

Cytokine Production ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Structure Activity ◽

Relationship Of

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IFN-β treatment modulates the CD28/CTLA-4-mediated pathway for IL-2 production in patients with relapsing -remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1094oa ◽

2004 ◽

Vol 10 (6) ◽

pp. 630-635 ◽

Cited By ~ 4

Author(s):

C Espejo ◽

L Brieva ◽

G Ruggiero ◽

J Río ◽

X Montalban ◽

...

Keyword(s):

Multiple Sclerosis ◽

Chronic Inflammatory Disease ◽

Autoimmune Response ◽

T Cell Proliferation ◽

Immunomodulatory Effects ◽

Cd25 Expression ◽

Relapsing Remitting ◽

The Central Nervous System ◽

Relapsing Remitting Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system probably mediated by Th1 lymphocytes. IFN-b is an established therapy for relapsing MS patients, although the mechanisms underlying its efficacy are yet to be well characterized. We determined IL-2 production, CD25 expression and T-cell proliferation from relapsing -remitting MS patients before and three months after starting therapy. A decrease in the percentage of CD80-induced IL-2-producing cells was observed after in vivo IFN-b treatment. These data support that one of the immunomodulatory effects of IFN-b treatment in MS may be a limitation of the autoimmune response modifying the CD80:CD28/CTLA-4 pathway.

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Immunomodulatory effects of the herbicide propanil on cytokine production in humans: In vivo and in vitro exposure

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2007.04.017 ◽

2007 ◽

Vol 222 (2) ◽

pp. 202-210 ◽

Cited By ~ 25

Author(s):

E CORSINI ◽

I CODECA ◽

S MANGIARATTI ◽

S BIRINDELLI ◽

C MINOIA ◽

...

Keyword(s):

Cytokine Production ◽

Immunomodulatory Effects ◽

In Vitro Exposure ◽

Herbicide Propanil

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Low sensitivity to glucocorticoid inhibition of in vitro Th17-related cytokine production in multiple sclerosis patients is related to elevated plasma lipopolysaccharide levels

Clinical Immunology ◽

10.1016/j.clim.2013.05.012 ◽

2013 ◽

Vol 148 (2) ◽

pp. 209-218 ◽

Cited By ~ 16

Author(s):

Bruna Teixeira ◽

Vera Carolina B. Bittencourt ◽

Thais B. Ferreira ◽

Taissa M. Kasahara ◽

Priscila O. Barros ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cytokine Production ◽

Elevated Plasma ◽

Low Sensitivity ◽

Multiple Sclerosis Patients

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Correlation between disease severity and in vitro cytokine production mediated by MSRV (Multiple Sclerosis associated RetroViral element) envelope protein in patients with multiple sclerosis

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2004.10.019 ◽

2005 ◽

Vol 160 (1-2) ◽

pp. 195-203 ◽

Cited By ~ 41

Author(s):

Alexandre Rolland ◽

Evelyne Jouvin-Marche ◽

Marina Saresella ◽

Pasquale Ferrante ◽

Rosella Cavaretta ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Severity ◽

Envelope Protein ◽

Cytokine Production

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Modulation of Th1/Th2 Cytokine Balance by Quercetin In Vitro

Medicines ◽

10.3390/medicines7080046 ◽

2020 ◽

Vol 7 (8) ◽

pp. 46

Author(s):

Yoshihito Tanaka ◽

Atsuko Furuta ◽

Kazuhito Asano ◽

Hitome Kobayashi

Keyword(s):

T Cells ◽

Mrna Expression ◽

Cd4 T Cells ◽

Cytokine Production ◽

Human Peripheral Blood ◽

Allergic Diseases ◽

Chronic Inflammatory Disease ◽

Culture Technique ◽

Cytokine Balance

Background: Allergic rhinitis (AR) is well known to be an IgE-mediated chronic inflammatory disease in the nasal wall, which is primarily mediated by Th2-type cytokines such as IL-4, IL-5, and IL-13. Although quercetin is also accepted to attenuate the development of allergic diseases such as AR, the influence of quercetin on Th2-type cytokine production is not well understood. The present study was designed to examine whether quercetin could attenuate the development of AR via the modulation of Th2-type cytokine production using an in vitro cell culture technique. Methods: Human peripheral-blood CD4+ T cells (1 × 106 cells/mL) were cultured with 10.0 ng/mL IL-4 in the presence or absence of quercetin. The levels of IL-5, IL-13, and INF-γ in 24 h culture supernatants were examined by ELISA. The influence of quercetin on the phosphorylation of transcription factors NF-κB and STAT6, and mRNA expression for cytokines were also examined by ELISA and RT-PCR, respectively. Results: Treatment of cells with quercetin at more than 5.0 μM inhibited the production of IL-5 and IL-13 from CD4+ T cells induced by IL-4 stimulation through the suppression of transcription factor activation and cytokine mRNA expression. On the other hand, quercetin at more than 5.0 μM abrogated the inhibitory action of IL-4 on INF-γ production from CD4+ T cells in vitro. Conclusions: The immunomodulatory effects of quercetin, especially on cytokine production, may be responsible, in part, for the mode of therapeutic action of quercetin on allergic diseases, including AR.

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