The N-Methyl-<i>D</i>-Aspartic Acid Receptor Antagonist Memantine Ameliorates and Delays the Development of Arthritis by Enhancing Regulatory T Cells

Abstract

The neuroendocrine impact on rheumatoid arthritis is not yet fully described although numerous neurotransmitters are shown to act as inflammatory modulators. One of these is the excitatory transmitter glutamate (Glu). In this study, the influence of the Glu receptor (GluR)-mediated effects on collagen-induced arthritis (CIA) was investigated. CIA was induced in DBA/1 mice by immunization with chicken collagen type II (CII). Mice were exposed to the following GluR antagonists: group 1, the N-methyl-D-aspartic acid (NMDA) receptor channel blocker memantine; group 2, the metabotropic GluR antagonist AIDA, and group 3, the excitatory amino acid receptor antagonist kynurenic acid (KA). Arthritis was evaluated clinically and histologically and compared to PBS-treated controls. The effects of treatment on T cell populations and the levels of anti-CII and anti-citrullinated peptide antibodies were evaluated. Memantine treatment significantly improved the course of CIA, reducing synovitis (p = 0.007) and the frequency of erosions (p = 0.007). Memantine treatment up-regulated the expression of Foxp3 in spleen CD4+ T cells followed by an increase in CD4+CD25+ regulatory T cells. The other GluR antagonists, AIDA and KA, had no effect on CIA. These results demonstrate that blockade of the NMDA receptor channel with memantine delays and attenuates the development of arthritis, probably by promoting the development of regulatory T lymphocytes.

Immunosuppression by N-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

“…Interestingly, repetitive application of a low-dose NMDAR antagonist to differentiating Th cells did not inhibit their antigen-induced proliferation but did diminish IL-2 and IFN-␥ production in Th1 cells as well as increased the production of IL-10 and IL-13 in Th2 cells; IL-10 and IL-13 are two cytokines associated with immunosuppressive functions (37,38). As IL-13 also exerts proinflammatory effects (as, for example, in asthma) (39), NMDAR antagonists in vivo may polarize the local environment toward either inflammation or immune suppression, depending on the cell type and disease setting (40).…”

Astrocytes Modulate the Polarization of CD4+ T Cells to Th1 Cells

“…Exposure to glutamate has been reported to modulate several functions and the proliferation of T cells by activating glutamate receptors expressed by T cells [38], [43], [44], [45], [46], [47], [48], [49]. Furthermore, the NMDA receptor antagonist memantine was reported to promote the development of Tregs [50]. A major function of astrocytes is to take up the neurotransmitter glutamate to prevent its accumulation in the synapse where it can reach levels sufficient to cause excitotoxicity in some neurological diseases.…”

Glutamate Signaling in Healthy and Diseased Bone

“…It is intriguing to note that a common treatment for RA is sulfasalazine, and this drug is particularly effective at inhibiting the system ${\text{X}}_{\text{c}}^{–}$ glutamate/cystine antiporter (Doxsee et al, 2007). Indeed, the importance of glutamate in arthritis is further highlighted using rodent arthritis models, as inhibition of NMDA with memantine delayed the onset of collagen-induced arthritis and reduced bone resorption in mice (Lindblad et al, 2012). The use of non-NMDA ionotropic receptor antagonists (Sluka et al, 1994), or a combination of NMDA and non-NMDA ionotropic receptor antagonists (Lam and Ng, 2010) also reduced swelling and alleviated pain symptoms in rat early arthritis models.…”