Neuroprotective And Confirmatory Study Of GLP-1/GIP/Gcg Triple Receptor Agonist On MPTP Model Mice With Parkinson’s Disease

Objective: To observe the protective effect of Triagonist,a GLP-1 / GIP / GCG triple receptor agonist,on motor symptom function in MPTP induced Parkinson’s disease mouse model and the changes of tyrosine hydroxylase(TH)and glial cell-derived neurotrophic factor(GDNF)expression in mouse brain.Methods: 24 8-week-old male C57 BL / 6 mice were randomly divided into four groups with 6 mice in each group;The following dosing regimen was carried out for 7consecutive days:(1)Blank control group(normal saline 0.1ml / day);(2).MPTP model group(MPTP 25 mg / kg / day,intraperitoneal injection);(3).Liraglutide +MPTP group(MPTP,25 mg / kg / day,intraperitoneal injection;after 30 minutes,liraglutide,25 nmol / kg / day,intraperitoneal injection);(4).Triagonist + MPTP group(MPTP,25 mg / kg / day,intraperitoneal injection;30 minutes later,Triagonist,10 nmol / kg / day,intraperitoneal injection).Blood glucose and body weight were monitored during administration,as well as pole climbing test and suspension test behavioral observation;After the behavioral experiment was completed,the mice were killed and the brain tissue was taken for immunohistochemical experiment.The positive dopamine nerve fibers marked by tyrosine hydroxylase in the striatum and glial cell-derived neurotrophic factor positive cells in the cerebral cortex were stained by immunopathology,The TH area ratio of positive dopamine nerve fibers and the area ratio of GDNF positive cells were measured by the positive staining area method in Image J win64 image analysis system.Results:(1)general state: MPTP group mice had limb tremor,vertical hair,straight tail,arched back,slow movement,limb stiffness,balance disorder and so on;The symptoms of dyskinesia in Triagonist group and liraglutide group were lighter than those in MPTP model group.(2)The effects of experimental drugs on body weight and blood glucose were not statistically significant(P > 0.05).(3)Pole climbing experiment: the completion time of pole climbing experiment in MPTP group was significantly longer than that in the control group(P < 0.001),and the pole climbing score was also higher than that in the control group.The results of repeated measurement complete random design analysis of variance showed that there was significant difference in the degree of motor ability injury among MPTP model group,liraglutide group and Triagonist group(P < 0.001).Through multiple comparative analysis,the motor ability injury of MPTP model group,liraglutide group and Triagonist group was statistically significant compared with that of normal saline control group(P < 0.001),and the degree of motor function injury of MPTP model group was higher than that of liraglutide group and Triagonist group(P <0.001).There was no significant difference in the improvement of pole climbing ability between Triagonist group and liraglutide group(P > 0.05).(4)Suspension test: there was significant difference in suspension score among control group,MPTP model group,liraglutide group and Triagonist group(P < 0.001).After multiple comparative analysis,the suspension capacity of MPTP model group,liraglutide group and Triagonist group was significantly lower than that of normal saline control group(P < 0.001).The difference between Triagonist group and MPTP group was significant(P < 0.001).(5)TH positive expression level: the expression of th in normal saline control group and Triagonist group was higher than that in other groups(P < 0.001),the expression of th in MPTP model group was significantly lower than that in other three groups(P < 0.001),the difference between liraglutide group and control group was small(P < 0.05),and there was no significant difference between Triagonist group and control group(P > 0.05).(6)GDNF positive expression level: the GDNF positive expression level of control group,liraglutide group and Triagonist group was significantly higher than that of MPTP model group(P < 0.001),but there was no significant difference between control group,liraglutide group and Triagonist group(P > 0.05).Conclusion: Triagonist can reduce the damage of toxic substance MPTP to dopamine neurons and nerve fibers,alleviate and improve the motor function of MPTP induced Parkinson’s disease model mice,and improve the levels of TH positive dopamine nerve fibers in striatum and GDNF positive cells in cerebral cortex.Triagonist has a lot of potential for the treatment and development of Parkinson’s disease.In the future,it can further study the treatment stability and specific mechanism of Parkinson’s disease.