Suppression of neuroinflammation by an allosteric agonist and positive allosteric modulator of the α7 nicotinic acetylcholine receptor GAT107

Abstract

Background The α7 nicotinic acetylcholine receptor (α7 nAChR) negatively regulates the synthesis and release of pro-inflammatory cytokines by immune cells. Our previous studies showed that in encephalitogenic T cells, α7 nAChR expression is upregulated and that activation of the cholinergic system can attenuate experimental autoimmune encephalomyelitis (EAE). GAT107 is an allosteric agonist and positive allosteric modulator (ago-PAM) of α7 nAChR that can produce persistent activation of this receptor. Therefore, in the present study, we investigated the effect of GAT107 on neuroinflammation in EAE, the animal model used for the study of multiple sclerosis (MS) via α7 nAChR, and the inflammatory pathways involved. Methods EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG35–55) in C57BL/6 mice. EAE mice were treated with the ago-PAM GAT107 or a placebo for 9 days, starting from the day of EAE induction. Clinical assessment and immunological evaluation of immune cells and cytokine production was performed. Results Following activation of the α7 nAChR by GAT107 during EAE, disease severity was significantly reduced by 70% and was correlated with a reduction in the extent of neuroinflammation in the CNS. The treatment reduced encephalitogenic T cell proliferation and the production of pro-inflammatory cytokines, as well as increased the production of the anti-inflammatory cytokine IL-10. Furthermore, the expression of immune cell markers was altered by GAT107 treatment, which induced a significant reduction in macrophages, dendritic cells, and B cells, as well as a reduction in anti-MOG35–55 antibodies. Additionally, GAT107 was found to directly activate α7 nAChR in murine macrophage RAW264.7 cells and in human PBMCs derived from MS patients and healthy donors. Conclusions Our results show that GAT107 can be a useful molecule for harnessing the cholinergic anti-inflammatory pathway for long-lasting and wide-ranging modulation and downregulation of neuroinflammation in EAE.

Neuroinflammation Modulation via α7 Nicotinic Acetylcholine Receptor and Its Chaperone, RIC-3

“…Nicotine stimulation up-regulated the expression of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on Tregs [38]. Our recent study also shows that activation of α7 nAChR up-regulated Foxp3 expression and, therefore, supports the role of α7 nAChR in regulating the immunomodulatory effects of Tregs during neuroinflammation [25].…”

“…Application of this drug following LPS stimulation of a murine macrophages cell line (RAW264.7) significantly reduced IL-6 secretion by these cells. These anti-inflammatory effects were eliminated by methyllycaconitine (MLA), a specific antagonist of α7 nAChR [25].…”

“…Murine and human T-cells express α7 nAChR, and this expression is increased following antigenic or mitogenic stimulation [28,32]. Our recent study on Experimental Autoimmune Encephalomyelitis (EAE) mice treated with the α7 nAChR ago-PAM, GAT107 showed reduced ex-vivo antigen specific induced T-cell proliferation and reduced secretion of pro-inflammatory cytokines (IL-17, IL-6 and IFNγ) while secretion of the anti-inflammatory cytokine, IL-10, was increased [25]. A similar result of reduced T-cell activity was shown when cholinergic agents such as Rivastigmine, an acetylcholine esterase inhibitor (ACHEI), or EN101 (an anti-sense oligonucleotide to exon 2 of AChE) were used.…”

“…Recently, we reported that the α7 ago-PAM GAT107 also affects B-cell function [25]. Mice with EAE showed a significant reduction in B-cell markers and lower pathogenic antibody production, following GAT107 treatment.…”

Homomeric and Heteromeric α7 Nicotinic Acetylcholine Receptors in Health and Some Central Nervous System Diseases

“…GAT107, B973B, and 4BP-TQS are examples of this class of molecules. GAT107 application to mice with induced experimental autoimmune encephalomyelitis (a model for multiple sclerosis) decreases the extent of neuroinflammation and reduces the severity of the disease [ 84 ]. In addition, dose-dependent antinociceptive effects of GAT107 in mouse models of acute and chronic pain were demonstrated.…”