Behavioral Valuation Of Chronic Unilateral Parkinson Disease Of Cynomolgus Monkeys Induced By MPTP

BackgroundParkinson's disease(PD)is now considered as multisystem neurodegenerative disease with non-motor and motor symptoms.PD prevalence was approximately 0.3% of the whole population and 1.7% of Chinese over the age of 65.Although a lot of attention has been focused on the mechanism of PD and few hypotheses have been put forward for the last two hundred years,the definite pathogenic mechanism still remains unknown.One of the reasons is due to lack of good animal model of primary PD which may lead to breakthrough in the development and clinical application of drug.Nonhuman primates,whose motor behavior characteristics are similar to human,are the best animal resource to establish PD model.The model established by neurotoxin,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)was the most approaching to the clinical features of PD,and made it an ideal PD model up to now.In prior reports,however,researchers paid more attentions tothe short term change of the modeling animals and few reports on the chronic changes of the animal models in the later stage.Therefore,little is known about a long term retrospective following up analysis and changes of motor and non-motor activities.ObjectiveThis dissertation intended to analyze a series of evaluation on motor and non-motor tasks,and PET imaging of the striatum of PD cynomolgus monkeys six years later after successfully established stable unilateral PD model by injecting MPTP into the left internal carotid of the animals.Behavioral tests including clinical scores of video record,upper limb fine motor,general motor activity,working memory,motor quantity and sleeping status using physical activity monitor(PAM)were carried out and compared to baseline data to investigate long-term changes of the motor and non-motor activities in non-human primate MPTP parkinsonism model.Method1 Though scores of video record covering the modeling period and PET imaging data of unilateral cynomolgus monkeys PD model by injecting MPTP into the left internal carotid to ensure the successful and stable cynomolgus monkeys PD model.2 Comparing the scores of video record six years later with the initial modeling period and elaborating the longitudinal change of constitutional symptom of cynomolgus monkeys induced by MPTP.3 Analysis the upper limb fine motor function by using the nine-hole feeding plate,MAP device and monkey chair of cynomolgus monkeys PD model ascompared to control group.4 To investigate the difference between the two groups in motor quantity and sleeping status using physical activity monitor(PAM)to analysis the daily motor quantity in the feeding cage.5 Finally,analysis the difference between the two groups in work memory-cognitive function of chronic unilateral cynomolgus monkeys PD modelby using DMTS cognitive test device.ResultIn the initial modeling period,the clinical scores of the video recording could reach over 10 points after intravenous injection of 2mg/kg MPTP within 3months.The PET imaging data analysis showed that the uptake ratio of lesioned side of corpus striatum with F18-AV133 was markedly decreased as compared to the normal side(about 46.4%).Six years later after lesion,the clinical scores of video recording(5.59±1.392 points)were still increased as compared to normal monkeys but significantly lower than that of the initial modeling period.While the normal control monkeys showed no differences in the time of getting food using left or right upper limb in the nine-hole feeding pate test(702.852 ± 44.307 ms,710.119±69.020 ms),the right upper limb(contralateral lesion side)still refused to get food and the time of the left upper limb(lesion side)was slower(954.397±98.909 ms,P<0.01)in unilateral PD monkeys than the controls.To further test the fine arm movement,the extensor and flexor movement of the arm,and the hand movement of getting food with the MAP device was tested and the times were all slower for the left arm and hand of the unilateral PD cynomolgus monkey(0.139±0.029 s,0.448±0.091 s,0.187±0.052s)than those ofthe control group(0.113 ± 0.021 s,0.289 ± 0.050 s,0.157 ± 0.048s;P<0.01).In monkey chair test in which one arm was restrained while recording how many times of the testing hand getting food within one minute,the times of left and right arm of the unilateral PD monkey were 8.40 ± 1.173,and 1.31 ± 0.485,respectively.The general motor activity during the day and night was recorded by PMA.It has showed that 24 h total motor activity counts and 12 h motor activity counts during the lighting were markedly decreased while the 12 hour motor activity during the night was significantly increased,indicating reduced general motor activity and sleep time.Work memory was tested with the DMTS cognitive test.The rates of accessing correct door pushing were not significant in the first day for both controls and the unilateral PD monkeys,when the delay time was 0s,but decreased by 55% and 47% for the unilateral PD monkeys,maintained over80% and 90% for the control monkeys,in the fifth and eighth day,respectively.When the delay time was randomly set for 5s,15 s,30s,the rate of accessing correct door pushing was mostly maintain around 50% for the unilateral PD monkeys which was significantly lower than that of the control monkeys that maintained around maximum the rate of 86% and 72% in 5s and 30 s delay tests.ConclusionOur results suggest that the behavioral deficits of motor function in the stable unilaterally lesioned PD model could last for at least six years after the initial modeling.This is consistent with the lasting damage to the striatum.In addition,we have also demonstrated that the unilateral PD model could also have lasting non-motor deficits including sleep and cognitive deficits in cynomolgus monkeys PD model.