Effects Of L-161982on Chemokines In Experimental Autoimmune Neuritis In Lewis Rats

Objective:Guillain-Barre syndrome (GBS) is an autoimmune peripheral neuropathy, pathological characteristic with peripheral nerve demyelinating lesions and small blood vessels inflammatory cells infiltrating, body symmetry flaccid limbs paralysis as the main clinical features. Experimental autoimmune neuritis (EAN) is an internationally recognized research animal model of GBS, a auxiliary1and17T cell (Thl/Th17) mediated autoimmune diseases, with peripheral nerve demyelination and a large number of inflammatory cells infiltration as the main pathological features. The infiltration of inflammatory cells including mononuclear macrophage, lymphocyte and granulocyte, proinflammatory cytokines (such as IFN-y, TNF-a, NO) and chemokines (MCP-1, MIP-lα, etc) plays a key role in its pathogenesis.In recent years, many studies suggest that prostaglandin E2(PGE2) is a kind of immunoactivator, may be acting on the EP4receptor to affect the differentiation of Thl and Th17two cells subgroups to participate in the immune inflammatory process of autoimmune diseases, thus we speculated that PGE2-EP4receptor antagonist has a therapeutic effect on EAN. In our previous studies found that the application of PGE2-EP4antagonist intervention EAN rats, L-161982can reduce the expression of IL-17and IFN-y in the sciatic nerves. Based on the important role of chemokines in GBS/EAN, this experiment observed the affect of PGE2-EP4antagonist L-161982on expressions of CXCL-12and MCP-1in EAN rats. Methods:LEAN was induced in Lewis rats by immunization with bovine peripheral myelin (BPM) and in an complete Freund’s adjuvant (CFA).2.Twenty-one EAN rats were randomly divided into treatment group A, treatment group B and control group. The two treatment groups were both cured with PGE2-EP4receptor antagonist L-161982(5mg/kg) intraperitoneally injected. Daily injected with L-161982from one day prior to the immunization to the eighth day after immunization as treatment group A. Daily injected with L-161982from the fifth to fourteenth day after immunization as treatment group B. The control group were gave the same volume of L-161982solvent DMSO everyday throughout the whole experimental stage.3.The clinical scores of each rat were observed everyday after immunization during the whole experiment. Using the immunohistochemical detect the expressions of CXCL-12and MCP-1in sciatic nerves, at day15post-immunization, that is the peak of the disease.4.Using SPSS18.0software for data statistical analysis, results were expressed by means±standard deviation.Results:1.Compared to control group, the two treatment groups could all significantly delay the onset time of EAN (P<0.05), reduce the height of clinical scores (P<0.05) and remarkably decrease the numbers of CXCL-12and MCP-1expression cells in the sciatic nerves (P<0.05).2.The comparisons of onset time、peak clinical grading and expressions of chemokines in EAN rats between the two treatment groups, there were significant differences(P<0.05).Conclusion:1. The application of L-161982could significantly delayed the onset time of EAN, reduced the height of clinical scores of EAN, suggesting that it has a therapeutic effect on peripheral nerve autoimmune disease. 2.The application of L-161982could reduced the expressions of CXCL-12and MCP-1in sciatic nerves, prompting PGE2-EP4receptor antagonist could inhibited the migration and activation of macrophage and T cell, reduced the generations of CXCL-12and MCP-1, so as to inhibited the immune inflammatory response, this may be one of the anti-inflammatory mechanism of L-161982.3. The application of L-161982in immune stage and onset phage all had therapeutic effect on EAN, and use L-161982in immune stage, the treatment effect is superior to onset stage.