Neuroprotective Effect Of A Novel GLP-1/GIP Double Receptor Agonist On MPTP Parkinson's Mice Model And Its Comparison With Liraglutide

Objective:Observe the neuroprotective effects of the novel dual agonist(DA3-CH)in the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)mouse model of Parkinson's disease model.To test the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market,liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine(MPTP)mouse model of PD.Methods:We have divided the male C57BL/6mice(20�22g)into into four groups.To test the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market,liraglutide(both drugs 25nmol/kg ip once-daily for 7 days)in the1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine(MPTP)mouse model of PD(25mg/kg ip daily).In the Rotarod and grip strength assessment,we compared their motor impairment.Immunohistochemistry was used to observe the numbers of TH positive cells,IBA-1positive cells and GFAP positive cells in substantia nigra,and the expression of TH in striatum by analyzing optical density of TH staining region.The dopamine synthesis as indicated by levels of tyrosine hydroxylase in the substantia nigra and striatum,the chronic inflammation response was shown in levels of activated microglia and astrocytes and levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor were tested by immunohistochemistry and western bolt.Results:1.Behavioral Tests: In the Rotarod and grip strength assessment,DA3-CH was superior to liraglutide in reversing the MPTP�induced motor impairment(p<0.001).2.Immunohistochemistry:2.1.Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum,and DA3-CH reversed this while liragutide only partially reversed this(p<0.001).2.2.The chronic inflammation response as shown in increased number of IBA-1-positive cells and GFAP-positive cells in substantia nigra and striatum was reduced by both drugs.DA3-CH is superior to liraglutide in reducing inflammation(p<0.001).2.3.The numbers of the neuroprotective growth factor Glial Derived Neurotrophic Factor(GDNF)-positive cells was much enhanced by both DA3-CH and liragutide(p<0.001)Compared with the liraglutide group,the number of GDNF-positive cells in substantia nigra and striatum of the DA3-CH group increased(p<0.001)3.Western blot: DA3-CH reversed the levels of tyrosine hydroxylase which was much reduced by MPTP in the substantia nigra and striatum significantly while liragutide only partially reversed this(p<0.001).The increased levels of activated microglia and astrocytes was reduced by both drugs(p<0.001).Importantly,expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor(GDNF)was much enhanced by both DA3-CH and liragutide(p<0.001).4.Conclusion:1.A novel GLP-1/GIP dual agonist DA3-CH showed the protective effects in the MPTP mouse model of Parkinson's disease by reducing inflammation and enhancing GDNF release.2.The combination of GLP-1 and GIP receptor activation is superior to single GLP-1receptor activation alone on the protection of PD mouse model.