Neuroprotective Effect Of Dual GLP-1/GIP Receptor Agonist DA-JC4 On Parkinson’s Disease Model And Its Comparison With Exendin-4

Objective:1.To investigate the protective effects of a dual GLP-1/GIP receptor agonist DA-JC4 on 6-OHDA-induced Parkinson’s disease cell model and it’s mechanisms.2.To compare the protective effects of the dual GLP-1/GIP receptor agonist DA-JC4 and the GLP-1 analogue on 6-OHDA-induced Parkinson’s disease model.Methods:1.The cultured SH-SY5 Y cells were randomly divided into 7 groups: 6-OHDA were treated with a concentration-depended manner(0μM、25μM、50μM、75μM、100μM、125μM,150μM)for 24 h.MTT test wound be performed after incubation to evaluate the appropriate concentration of the 6-OHDA toxicity.2.The control group,the exendin-4 group,and DA-JC4 group were set up.MTT test wound be performed after the incubation;The cultured SH-SY5 Y cells were randomly divided into 8 groups:(1)Control group;(2)6-OHDA;(3)6-OHDA+ exendin-4(1nM),(4)6-OHDA+exendin-4(10nM),(5)6-OHDA + exendin-4(100nM);(6)6-OHDA +DA-JC4(1nM),(7)6-OHDA + DA-JC4(10nM),(8)6-OHDA +DA-JC4(100nM).MTTtest wound be performed after the incubation.3.The cultured SH-SY5 Y cells were randomly divided into 6 groups:(1)Controlgroup;(2)exendin-4 group;(3)DA-JC4 group;(4)6-OHDA group;(5)6-OHDA+exendin-4 group;(6)6-OHDA+DA-JC4 group。The expression of the proteins(LC3,ATG7,and P62)related to autophagy were detected by western blot.Results:1.The cell viability of group was decreased following the increasing concentration of 6-OHDA treatment(P<0.05).2.There was no significant difference in cell viability between the DA-JC4 group alone(or exendin-4 group alone)and the control group;6-OHDA significantly decreased the viability of SH-SY5 Y cells(P>0.05);and the addition of DA-JC4(or exendin-4)partially blocked the SH-SY5 Y toxicity induced by 6-OHDA(P<0.05);The effect of the DA-JC4 is better than DA-JC4(P<0.05).3.The expressions of autophagy-related proteins LC3,ATG7 and P62 were determined.It was shown that the 6-OHDA model group reduced autophagy expression in SH-SY5 Y cells(P<0.05);both DA-JC4 and exendin-4 alleviated 6-OHDA-induced SH-SY5 Y cells autophagy injury(P<0.05);DA-JC4 has a more protective effect on autophagy injury than exendin-4(P<0.05).Conclusion:1.The novel GLP-1 receptor agonist DA-JC4 and GLP-1 single receptor agonist exendin-4 can protect 6-OHDA-induced SH-SY5 Y cell injury,which may ameliorate6-OHDA induced autophagy damage.2.The combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone on the protection of PD cell model.