DMXB-Anabaseine

Parkinson's disease (PD) is a neurological disorder that causes a gradual decrease in mobility. Abnormal α-synuclein (α-syn) levels and aggregation contribute to PD development. The dissemination of α-synuclein pathology via the gut-brain axis has emerged as a critical aspect in α-synucleinopathies, including PD. Recently, α7 nicotinic acetylcholine receptor (α7nAchR) agonists have been proposed as promising agents for treating PD, owing to their biological properties such as anti-inflammatory effects. This study aims to investigate whether activation of α7nAchR improves α-synuclein pathology in the brain and gut of a mouse model of PD. We found that α7nAchR agonists, GTS-21 and PNU-282987, induced behavioral recovery and improved nigrostriatal dopaminergic neurotransmission in a subacute MPTP mouse model of PD. In addition, GTS-21 and PNU-282987 facilitated α-syn clearance in the brain and distal colon, as evidenced by a considerable reduction in the accumulation of pathogenic forms of α-syn. Accordingly, GTS-21 and PNU-282987 were found to promote the AMPK-mTOR autophagy signaling pathway. Furthermore, GTS-21 and PNU-282987 exerted anti-inflammatory effects, reducing the levels of proinflammatory mediators such as inducible nitric oxide synthase, interleukin-6, and tumor necrosis factor-α in both the brain and gut. To validate the specific effects of α7nAchR agonists, subacute MPTP mice were pretreated with methyllycaconitine (MLA), a selective α7nAchR antagonist before GTS-21 administration. Pretreatment with MLA abolished the GTS-21-elicited behavioral recovery, α-syn clearance, and anti-inflammatory effects in the brain and gut. Therefore, α7nAchR activation may be a potential candidate strategy for the treatment of PD by altering α-syn aggregation in the brain and gut.

Previous research has demonstrated ɑ7nAch receptor (ɑ7nAchR) agonists to provide benefit for rheumatoid arthritis (RA) patients. However, the immunological mechanism of action for these ɑ7nAchR agonists has not been elucidated. Herein, the effect of GTS-21, a selective ɑ7nAchR agonist, on the differentiation of Th17 and Th2 cells was assessed. CD4 + T cells were obtained from the peripheral blood mononuclear cells (PBMCs) of RA patients and healthy donors. CD4 + T cells were separately differentiated into Th2 or Th17 cells with or without GTS-21 and with or without alpha-bungarotoxin (ɑBgt) (a ɑ7nAchR antagonist). The proportions of Th17 and Th2 cells were assessed by flow cytometry. Levels of the T cell cytokines, IL-17A and IL-4, were assessed by ELISA. Specific transcription factors, retinoic orphan receptor c (RORc), and GATA Binding Protein 3 (GATA-3) were detected by western blot. GTS-21 reduced IL-17A and increased IL-4 production by RA PBMCs. GTS-21 reduced the percentage of Th17 cells and increased the percentage of Th2 cells during Th17 and Th2 differentiation, respectively. GTS-21 downregulated RA CD4 + T cells RORc levels and reduced the secretion of IL-17A during Th17 differentiation. GTS-21 upregulated RA CD4 + T cells GATA3 and promoted IL-4 production during Th2 differentiation. ɑ-Bgt blocked the effects of GTS-21 during Th17 and Th2 differentiation. These results demonstrated that GTS-21 suppressed RA Th17 differentiation and promoted Th2 differentiation. As such, the use of GTS-21 may be a new therapeutic approach by which to treat RA patients. Key Points • GTS-21 suppressed RA Th17 differentiation and promoted Th2 differentiation via acting on ɑ7nAchR. • The protective effect of GTS-21 on RA may be related to its regulation of Th cell subsets.