Combination treatment of mice with crx-153 (nortriptyline and desloratadine) decreases the severity of experimental autoimmune encephalomyelitis

Abstract

Pro-inflammatory CD4+ T cell mediated autoimmune diseases, such as multiple sclerosis, are hypothesized to be initiated and maintained by self-reactive interferon-gamma (IFN-γ) and interleukin-17 (IL-17) producing CD4+ T cells. Previous studies have shown moderate to significant alterations in inflammatory T cell responses and potentially treatment of autoimmune disease by administration of anti-histamine or tricyclic antidepressants alone. The goal of the present study was to determine if treatment of PLP139–151-induced relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) in SJL/J mice with a combination of two FDA approved drugs for other indications could decrease R-EAE disease. The findings show that combination treatment with desloratadine and nortriptyline decreases the mean clinical score, disease relapse frequency, and number of CD4+ T cells infiltrating into the CNS. In addition, combination treatment of PLP139–151 primed mice decreases the level of IFN-γ and IL-17 secreted via a decrease in both the number of cells secreting and the amount of cytokine secreted per cell following PLP139–151 reactivation ex vivo. This is in contrast to an increase in the level of IL-4 produced and the number of IL-4 secreting cells. The data also show that combination treatment with desloratadine and nortriptyline inhibits the production of IFN-γ and IL-17 produced by naive CD4+ T cells activated in the presence of Th1 cell- and Th17-cell promoting conditions, while increasing the level of IL-4 produced by naive CD4+ T cells activated in the presence of Th2 cell-promoting conditions. The present findings suggest a novel method for the development of a putative autoimmune therapy.

Antidepressants on Multiple Sclerosis: A Review of In Vitro and In Vivo Models

“…In addition, pharmacological intervention with chronic application of amitriptyline in the mild MOG-EAE mice model resulted in a decreased startle reaction and increased hippocampal norepinephrine levels. Another group of researchers ( 57 ) utilized the combination treatment or nortriptyline (TCA) and desloratadine (antihistamine) to assess their therapeutic potential on EAE mice. This combination treatment moderated EAE severity by reducing CD4+T cell infiltration in the CNS and suppressing IFN-γ, IL-17 secretion, while boosting anti-inflammatory IL-4 levels.…”

“…These findings are aligned with other observations supporting that imipramine reduces plasma levels of IL-4 and clomipramine decreases m-RNA expression levels of IFN-γ, TNF-a, IL-17 and chemokine CCL-2. Overproduction of chemokine CCL-5 (also known as RANTES) was mitigated by desipramine, thus restoring glutamate exocytosis and presynaptic cortical defects ( 57 ).…”

Extracellular adenosine induces hypersecretion of IL-17A by T-helper 17 cells through the adenosine A2a receptor

“…Mice also received oral water or an A2aR antagonist (Istradefylline; 6 μg/mouse) once every 2 days from Day −7 to Day +18 after immunization with PLP peptide (Day 0). Mice were examined daily for signs of EAE, which were graded as described ( Podojil et al, 2011 ).…”

Extracellular adenosine induces hypersecretion of IL-17A by T-helper 17 cells through the adenosine A2a receptor to promote neutrophilic inflammation

“…Mice also received oral PBS(-) or an A2aR antagonist (Istradefylline) (6 µg/mouse) once every 2 days from Day -7 to Day +18 after immunization with PLP peptide (Day 0). Mice were examined daily for signs of EAE, which were graded as described (24).…”