The Effects And Mechanisms Of Anbainuo On Relieving Pain In Rheumatoid Arthritis

In the present,newer and more targeted biologic drugs directed at specific molecules and patterns involved in the pathogenesis of RA have been recently introduced in management of RA.Recently,it has been realized that tumor necrosis factor-a(TNF-a)is one of the key causative agents in mediating the pathogenesis of RA.The biological disease-modifying antirheumatic drug(bDMARD)targeting TNF-a has revolutionized treatment of RA,and clinical remission becomes a realistic treatment goal.Recently,it has been paid close attention to targeting TNF-a by bDMARD for treatment of RA.Several bDMARDs have been developed and applied in clinic for treating RA disease.In some RA patients,the outcomes of these biologics are not succedaneous by other agents.Even more gratifying is that with the rapid development of biotechnology and biopharmaceutical technology in China,biological agents targeted for TNF-a treatment of RA have also been developed and applied to clinic to the target of domestic RA patients in China.It has become possible to carry out RA treatment in China in general or comprehensive application of these drugs,but it is not enough to understand the specific mechanism of the application of these drugs in the management of RA.The effect of observation is still lack of due experience,the judgment of the efficacy of no predictive assessment of the means,indicators,standards or guidelines to follow.Hence,primary cultured dorsal root ganglion(DRG)neurons were used to determine the effects of TNF-α at different concentrations on the expression of transient receptor potential vanilloid type1(TRPV1)and transient receptor potential ankyrin 1(TRPA1)in the present study.Type Ⅱ collagen induced arthritis rat model was used to determine the effects of TNF-α inhibitor anbainuo(ABN)on the analgesic activity and the expression of TRPV1 and TRPA1 in DRG neurons of this rat model.The interactions of TNF-αand TRPV1 or TRPA1 on the analgesic effects were proposed in this study.The analgesic activity and therapeutic effects of ABN on active RA patients who have experienced methotrexate(MTX)combined with other conventional disease-modifying antirheumatic drugs(cDMARDs)and have inadequate response to these drugs.The data of the present study will provide novel theoretical and clinical evidence for relieving pain,hindering disease progression,and acquiring better prognosis.Part Ⅰ The effects of TNF-α on TRPV1 and TRPA1 expression in cultured dorsal root ganglion neuronsTNF-α signaling system in mediating inflammatory nociceptive(pain)sensitization is complicated.TRPV1,a non-selective cation channel,mediates not only neurogenic inflammation and oxidative stress,but also nerve injury induced neuropathic pain.TRPA1 is an excitatory ion channel that functions as a cellular sensor and works as initiators and gatekeepers of nociception and inflammation.TRPV1 and TRPA1 could detect a wide range of proalgesic agents such asenvironmental irritants and endogenous products of inflammation and oxidative stress.Via the primary sensory neurons these sentinels convey information to the central nervous system(CNS),where perceptions of nociception or sensory irritation are generated.From the point of view,TNF-α has been implicated in the development and progression of RA.TRPV1 and TRPA1,expressed in DRG neurons,are the key molecules in mediating peripheral pain signals.To determine the interactions of TNF-a and TRPV1 or TRPA1 in mediating neuropathic pain,the expression of TRPV1 and TRPA1 in primary cultured DRG neurons with different concentrations of TNF-α stimulation was investigated in the present study.The results showed that lower concentration TNF-a(1 ng/ml)promoted neurite outgrowth of DRG neurons;whereas higher concentration TNF-a(10 ng/ml)inhibited neurite outgrowth of DRG neurons.Lower concentration TNF-a(1 ng/ml)elevated the proportion of TRPV1-positive neurons;higher concentration TNF-a(10 ng/ml)decreased the proportion of TRPV1-positive neurons.Lower concentration TNF-a(1 ng/ml)elevated the proportion of TRPA1-positive neurons;higher concentration TNF-a(10 ng/ml)decreased the proportion of TRPA1-positive neurons.These results indicated that TNF-a mediated actions of primary sensory neurons are diverse in different pathophysiological conditions.This in vitro model provided theoretical and experimental evidence for further exploring the interactions of TNF-a and TRPV1 or TRPA1 in mediating the development and progression inflammatory reaction and pain.Part Ⅱ The effects of anbainuo on relieving pain behaviors in rats with type Ⅱ collagen induced arthritisTo date,various biologic targeting treatments for RA have been developed;however,accurate targeted therapy for different active disease condition has not been established.TNF-a is the marker of inflammation and acts as a proinflammatory cytokine that plays an important role in the pathogenesis of RA.TNF-a inhibitor ABN prevents TNF-a-induced inflammatory reaction,but there is a lack of direct evidence to show whether TNF-a signaling affects the expression and activity of TRPV1 and TRPA1.In the present study,type Ⅱ collagen induced arthritis rat model was used to determine the effects of TNF-α inhibitor ABN on relieving neuropathic pain behaviors.The interactions of the expression of TRPV1 and TRPA1 in DRG neurons and TNF-a inhibitor ABN in this arthritis rat model were also investigated.The results showed that TNF-a inhibitor ABN effectively improved the neuropathic pain behaviors induced type II collagen.Type Ⅱ collagen induced inflammatory reaction resulted in the up-regulation of TRPV1 and TRPA1 and their mRNAs.Treatment with TNF-a inhibitor ABN could down regulate TRPV1 and TRPA1 and their mRNAs induced type II collagen.According to thesedata,it is proposed that TRPV1 and TRPA1 are involved in type II collagen induced inflammatory reaction,which correlates with the up-regulation of TNF-a.TNF-a inhibitor ABN may block the neurotoxicity of the up-regulated TNF-a and then interfere with the expression of TRPV1 and TRPA1 in DRG neurons.TNF-a signaling system may be the effective therapeutic target in treatment of RA by its wide range improving neuropathic pain behaviors in relating to TRPV1 and TRPA1.Part Ⅲ The therapeutic effects of anbainuo on active rheumatoid arthritis patientsTNF-a inhibitors by targeting the activity of TNF-a have revolutionized treatment of RA.Clinical remission is now realistic targets,achieved by a large proportion of RA patients,and rapid and appropriate induction of remission by intensive treatment with bDMARD and MTX is prerequisite to halt joint damage and functional disabilities.According to the chronic inflammatory etiology and the key actions of proinflammatory cytokine TNF-a in mediating the development and progression of RA,the therapeutic effects of TNF-a inhibitor ABN on active RApatients who have experienced MTX combined with other cDMARDs and have inadequate response were observed at 2 w,6 w,10 w,18 w,and 24 w after treatment with ABN combined with MTX.The morning stiffness time,number of tender joints,tenderness index,swelling joints,swelling index,rest pain,Health Assessment Questionnaire(HAQ),pain VAS score,physician satisfaction VAS score,erythrocyte sedimentation rate(ESR),and C-reactive protein(CRP)were evaluated at each time point.The results showed that all the parameters or indicators of morning stiffness time,number of tender joints,tenderness index,swelling joints,swelling index,rest pain,HAQ,pain VAS score,physician satisfaction VAS score,ESR,and CRP were improved along with treatment time prolonged.These data imply that ABN by TNF-a has definite effect on active RA.