Gowayed_2019_Biochem.Pharmacol__113665

OBJECTIVE: The evolution of the "cholinergic anti-inflammatory pathway" and the fact that the alpha 7 subunit of the nicotinic acetylcholine receptor (alpha7nAChR) is present in the spleen, joint and on the surface of lymphocytes, opened up the prospective in this study of targeting the alpha7nAChR by the anticholinesterase and cholinergic drug, galantamine, to control inflammation in rheumatoid arthritis (RA). METHODS: Twelve-adjuvant arthritic rats were exposed to the selective alpha7nAChR blocker methylcaconitine citrate 15 min before galantamine treatment. As control, six adjuvant arthritic rats were treated with galantamine and six others were untreated. After 5 days TNF-alpha levels were assessed in spleen and joints, while reduced glutathione was measured in blood and joint tissue. In the second part, magnetically sorted CD4+Tcells from peripheral blood mononuclear cells of RA patients and healthy donors were used to sort CD4+CD25- primary T cells (Tresp) and CD4+CD25+CD127low Tregs. The suppressive function of Tregs was investigated after incubation with galantamine using flow cytometry. Cell culture supernatants were analyzed for TNF-alpha and IL-10 levels after three days incubation period of Tregs with Tresp. The effect of galantamine on Tregs was then blocked by alpha-Bungarotoxin and the same assay has been repeated. RESULTS & CONCLUSION: Selective alpha7nAChR blockade interrupted the anti-inflammatory effect of galantamine in the spleen and joints of arthritic rats. In healthy donors, galantamine could strengthen the suppressive activity of Tregs; while in RA patients it did not modulate the function of Tregs significantly. Further studies are necessary to investigate whether modulation of the cholinergic nervous system, especially alpha7nAChR, could have impact on the disturbed immune system in RA, which may open up a new treatment option of autoimmune diseases.