Immunosuppressive Activity And New Indications Exploration Of The Antimalarial Drug Naphthoquine

Autoimmune diseases(ADs)are diseases that arise when the body reacts to its own antigens due to an abnormal autoimmune response.Rheumatoid arthritis(RA)and systemic lupus erythematosus(SLE)are two common refractory ADs for which existing treatments have significant side effects,individual differences or are expensive,and therefore new treatments still need to be developed.Naphthoquine(NFQ)belongs to the same quinoline class of antimalarials as HCQ and CQ.The purpose of this project is to evaluate the immunosuppressive activity of NFQ in vitro and in vivo,to investigate the therapeutic effect of NFQ in animal models of ADs,explore the possibility of using old drugs for new purposes,and provide references for the development of therapeutic drugs for ADs.The in vitro immunosuppressive activity of NFQ and the control drugs CQ and HCQ were first investigated in an in vitro assay using mitogen-induced splenic lymphocyte activation and proliferation response and LPS-induced RAW 264.7cytokine secretion.The results showed that NFQ significantly inhibited the proliferation response of splenic lymphocytes induced by Con A and LPS,and its selection index of biological effects was better than CQ and HCQ.NFQ had better immunosuppressive activity in vitro.Besides,NFQ,as well as CQ and HCQ,showed some inhibitory effects on LPS-induced inflammatory factor secretion in RAW 264.7cells.The in vivo immunosuppressive activities of NFQ and HCQ were examined in the air pouch models and OVA assay models.The results showed that NFQ administration significantly inhibited LPS-induced macrophage infiltration in mouse air pouch and suppressed inflammatory cytokine secretion.In addition,NFQ suppressed antigen-specific lymphocyte proliferation and antibody secretion in OVA mice.Based on the high immunosuppressive activity of NFQ in vitro and in vivo,its therapeutic effects on arthritis were subsequently evaluated in collagen-induced mouse arthritis model and adjuvant-induced rat arthritis model.It’s therapeutic effects on SLE were evaluated in MRL/lpr spontaneous lups mouse model.The results of pharmacodynamic evaluation showed that NFQ significantly improved arthritis indications such as joint deformation and swelling,reduced arthritis clinical scores and bone erosion in arthritic mice and exerted therapeutic effects by inhibiting TLRsmediated B-cell activation.NFQ is more effective than HCQ in treatment;NFQ administration did not significantly reduce the albuminuria level and albuminuriacreatinine ratio in MRL/lpr mice,but significantly reduced their serum pathogenic levels of autoantibodies anti-ds DNA antibody and ANA.In conclusion,this study systematically evaluated the immunosuppressive activity of the antimalarial drug NFQ and its therapeutic effects in animal models of RA and SLE,and the results showed that NFQ has good immunosuppressive activity and its efficacy is significantly better than that of the clinical arthritis and lupus treatment drug HCQ.NFQ is expected to be developed as a therapeutic candidate for autoimmune diseases,especially for the treatment of SLE complicated by arthritis.