The Effect And Mechanisms Of Novel Dual-GLP-1/GIP Receptor Agonist DA3-CH On Epileptogenesis In The Rat After Status Epilepticus

Objective:To explore the effect and potential mechanisms of novel dual-glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide?GLP-1/GIP?receptor agonist DA3-CH on epileptogenesis in the rat after status epilepticus?SE?induced by pilocarpine.Methods:A total of 108 healthy adult male Sprague-Dawley?SD?rats weighing 250³00g were randomly divided into a normal control group?NS group,n=12?,a SE model group?SE group,n=48?,and a DA3-CH-treated group?SE+DA3 group,n=48?.SE group and SE+DA3 group respectively composes of 4 subgroups?n=12 per subgroup?,with each subgroup corresponding to the different time point after the onset of SE:12h,1d,3d,7d.Pilocarpine(30mg?kg^-1)was administered intraperitoneally?ip.?to induce SE model.After successfully induced,the rats of SE+DA3 group were injected DA3-CH(10nmol?kg^-1,ip.)once-daily before the animals'meals,while the rats of NS group and SE group were received the same volume of normal saline instead of the DA3-CH.The rats of each subgroup were detected the fasting glucose levels of tail vein and then sacrificed to take out the brain tissue at 12h,1d,3d,7d after SE.Expression of GFAP?the biomarker of astrocytic activation?,Iba-1?the biomarker of microglial activation?,IL-1?and TNF-??pro-inflammatory cytokines?,Bax and Bcl-2?apoptosis-related proteins?and NeuN in hippocampus were detected by immunohistochemistry and western blot analysis.Results:?1?There is no statistical significance in the fasting glucose levels of tail vein between subgroups of NS group,SE group and SE+DA3 group?P>0.05?.?2?The results of immunohistochemistry and western blot analysis show that the difference in hippocampal expression of GFAP,Iba-1,IL-1?,TNF-?,Bax,Bcl-2 and NeuN is statistically significant between subgroups of NS group,SE group and SE+DA3 group?P<0.001?;Compared with NS group,SE group show increased expression of GFAP,Iba-1,IL-1?,TNF-?,Bax and Bcl-2 as well as decreased expression of NeuN in hippocampus;Treatment with DA3-CH show decreased expression of GFAP,Iba-1,IL-1?,TNF-?and Bax as well as increased expression of Bcl-2 and NeuN in hippocampus compared with SE group.Conclusion:Novel dual-GLP-1/GIP receptor agonist DA3-CH has anti-epileptogenesis effect possibly by suppressing neuro-inflammation reaction,apoptosis and neuronal loss induced by SE.