ARR-17779

Inflammation plays a central role in stroke-induced brain injury. The alpha7 nicotinic acetylcholine receptor (α7nAChR) can modulate immune responses in both the periphery and the brain. The aims of the present study were to investigate α7nAChR expression in different brain regions and evaluate the potential effect of the selective α7nAChR agonist AR-R17779 on ischemia–reperfusion brain injury in mice. Droplet digital PCR (ddPCR) was used to evaluate the absolute expression of the gene encoding α7nAChR (Chrna7) in hippocampus, striatum, thalamus and cortex in adult, naïve mice. Mice subjected to transient middle cerebral artery occlusion (tMCAO) or sham surgery were treated with α7nAChR agonist AR-R17779 (12 mg/kg) or saline once daily for 5 days. Infarct size and microglial activation 7 days after tMCAO were analyzed using immunohistochemistry. Chrna7 expression was found in all analyzed brain regions in naïve mice with the highest expression in cortex and hippocampus. At sacrifice, white blood cell count was significantly decreased in AR-R17779 treated mice compared with saline controls in the sham groups, although, no effect was seen in the tMCAO groups. Brain injury and microglial activation were evident 7 days after tMCAO. However, no difference was found between mice treated with saline or AR-R17779. In conclusion, α7nAChR expression varies in different brain regions and, despite a decrease in white blood cells in sham mice receiving AR-R17779, this compound does not affect stroke-induced brain injury.

Background and purpose: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint destruction. Excessive proliferation of fibroblast-like synoviocytes (FLS) and over-expression of angiogenic factors play a crucial role in pannus formation and joint destruction in RA. Clarification of the role of cholinergic agonists in modulation of inflammation and immune system reactions is progressively ongoing. In this study, the anti-angiogenic effect of two cholinergic agonists, nicotine and ARR17779, on human FLS, and monocytic cell lines (U937) was evaluated.Experimental approach: The cells were cultured in DMEM supplemented with 10% FBS and treated with different doses of nicotine and ARR17779 in the presence of TNF-α, LPS, and IFN-γ. After 48 h, cell number was counted in different groups. After RNA extraction, cDNA was synthesized and the expression of VEGF and MMPs has been evaluated by real-time PCR using specific primers and probes. VEGF was assayed in U937 cell line supernatant using ELISA method.Key results: Both nicotine and ARR17779 inhibited FLS and U937 cell proliferation. Cholinergic agonists reduced the expression of MMPs and VEGF. VEGF level in supernatant of U937 cells treated with cholinergic agonists was also reduced.Conclusion and implications: Our results suggest that cholinergic agonists can modulate pathological conditions related to pannus formation in in-vitro conditions. Based on these results, cholinergic agonists can be considered as novel therapeutic options in RA. Further animal studies are needed before introducing these agents into clinical uses.