摘要
目的:评价长期慢性1-甲基-4-苯基-1,2,3,6-四氢吡啶( 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)诱导的帕金森病(Parkinson’s disease,PD)食蟹猴模型(左侧颈内动脉注射MPTP诱导成模后7年)运动与认知记忆功能障碍状态以及多巴丝肼和多奈哌齐干预后的影响。方法:5只慢性PD模型食蟹猴,5只同年龄段健康食蟹猴作为正常对照。分别进行行为学评价,包括Kurlan评分量表评价PD症状严重程度;取食实验(pick up test,PUT)检测上肢精细运动;PAM(physical activity monitoring,PAM)分析24 h运动活动总量及12 h睡眠时段运动活动量的状况。此外,延迟匹配样品比对测试(delay matching-to-sample,DMTS)检测短时认知记忆功能。依次给予多巴丝肼口服10 d,每天2次,每次250 mg,间隔10 d后给予多奈哌齐口服干预14 d,每天1次,每次5 mg,并在分别给予两种药物干预后,测试上述行为学指标变化。结果:长期慢性PD模型Kurlan评分[(4.10±1.01)分]显著高于正常对照组(0分)( P<0.01);右侧上肢与正常对照相比,虽有随意运动但均不能完成取食动作( P<0.01),左侧上肢取食时长[(23.14±7.96)s]与正常对照组[(12.52±2.71)s]相比,差异无统计学意义( P>0.05);24 h运动活动总量[(23 531.75±9 065.85)]与正常对照组[(52 750.34±27 598.89)]相比,差异无统计学意义( P>0.05),12 h睡眠时段运动活动总量[(2 911.34±1 845.47)]与正常组[(3 310.67±1 721.63)]相比,差异无统计学意义( P>0.05);DMTS 5 s、10 s、15 s、30 s延迟后的正确率分别为(61.60±9.21)%、(51.20±11.80)%、(49.60±8.29)%、(60.80±4.38)%,较正常对照组(分别为(96.80±3.35)%、(84.80±8.67)%、(80.80±7.69)%、(74.40±4.56)%)相比显著降低( P<0.01、 P<0.05、 P<0.01、 P<0.01)。给予多巴丝肼干预后,Kurlan评分为(2.60±0.38)分,与给药前[(4.10±1.01)分]相比,差异无统计学意义( P>0.05);右侧上肢仍不能完成操作,左侧上肢取食时长[(15.40±4.14)s]较之给药前[(23.14±7.96)s]缩短( P<0.05);24 h动物运动活动总量[(44 128.25±16 464.71)]高于给药前基线[(23 531.75±9 065.85)]( P<0.05),12 h睡眠时运动活动量(4 931.84±2 304.06)与给药前基线(2 911.34±1 845.47)相比,差异无统计学意义( P>0.05);DMTS 5 s、10 s、15 s、30 s延迟正确率与给药前同样延迟的正确率相比,均差异无统计学意义(均 P>0.05)。给予多奈哌齐干预后与给药前相比,各行为学指标均差异无统计学意义(均 P>0.05)。 结论:长期慢性PD模型仍存在PD症状以及不同程度的运动与认知记忆障碍。多巴丝肼干预后可改善运动损害行为,表明慢性长期PD模型动物脑内多巴胺神经系统功损害持续存在;多奈哌齐干预后对PD症状、运动与认知记忆均无影响,提示造成慢性PD模型食蟹猴的认知记忆障碍的潜在机理与阿尔茨海默病不同。
Objective To evaluate the function of motor behavior and cognitive working memory of long-term Parkinson’s disease(PD)cynomolgus monkey,which has been seven years after induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)injection through internal carotid artery and investigate the effects of benserazide-levodopa and donepezil intervention on above mentioned dysfunction of motor behavior and cognitive working memory.Methods Five long-term cynomolgus monkey PD models and five healthy ones with the same as normal control,behavioral evaluation was performed respectively,including Kurlan rating scale for evaluating the severity of PD symptoms,pick up test(PUT)for detecting the upper limb fine motor skills;physical activity monitoring(PAM)for analyzing the 24 h whole day locomotion exercise,and 12 h locomotion activity during sleep.In addition,delay matching-to-sample(DMTS)for detecting cognitive working memory.Furthermore,benserazide-levodopa was administered orally for 10 days,twice a day,250 mg each time,and after 10 days interval,and donepezil was orally administered for 14 days,once a day,5 mg each time,and all above behavioral indicators were tested after madopar and donepezil intervention respectively.Results Kurlan score(4.10±1.01)in the long-term chronic PD model group was significantly increased than that in the normal control(0)(P<0.01).Compared with the normal control,PUT test for retrieving the food items was not able to be performed with the right upper limb(P<0.01).The time for picking up the food items in left upper limbs((23.14±7.96)s)was no significant difference from that in normal control group((12.52±2.71)s)(P>0.05).The 24 h total locomotion(23531.75±9065.85)was not different from that normal control group(52750.34±27598.89)(P>0.05).The 12 h total locomotor activity during sleep period(2911.34±1845.47)was not different from the normal control group(3310.67±1721.63).The DMTS correction rate in long-term chronic PD group at 5 s,10 s,15 s,and 30 s delay were(61.60±9.21)%,(51.20±11.80)%,(49.60±8.29)%,(60.80±4.38)%,respectively,and was significantly decreased(P<0.01,P<0.05,P<0.01,P<0.01)compared with those in normal control group((96.80±3.35)%,(84.80±8.67)%,(80.80±7.69)%,(74.40±4.56)%,respectively).After intervention of benserazide-levodopa,there was no significant difference in Kurlan score(2.60±0.38)compared with that before intervention(4.10±1.01)(P>0.05);the PUT test in right upper limb was still not able to be performed,the time for retrieving the food items in left upper limb((15.40±4.14)s)was less than that before administration((23.14±7.96)s)(P<0.05);the 24 h total locomotion activity(44128.25±16464.71)was increasesd than that before intervention(23531.75±9065.85)(P<0.05).There was no significant difference in 12 h locomotion activity during sleep(4931.84±2304.06)compared with that before madopar administration(2911.34±1845.47)(P>0.05).There was no significant difference between the DMTS correction rate at 5 s,10 s,15 s,30 s before and after madopar intervention(all P>0.05).There was no difference in all behavioral indicators(all P>0.05)between before and sfter donepezil administration.Conclusion Long-term chronic PD monkeys still exist symptoms and motor behavior and cognitive working memory impairment.The benserazide-levodopa intervention can improve the motor behavior and cognitive working memory dysfunction,indicating that the lesion of functional integrity of dopaminergic system is still exist in long-term chronic Parkinsonian monkeys.Donepezil intervention is not able to reverse the motor and cognitive working memory,implying that mechanism underlying the cognitive memory impairment of PD monkeys is different from that in Alzheimer's disease.
作者
杜媛媛
罗斌斌
岳峰
Du Yuanyuan;Luo Binbin;Yue Feng(Key Laboratory of Longevity and Ageing-Related Diseases,Ministry of Education,Center for Translational Medicine,School of preclinical Medicine,Guangxi Medical University,Nanning 530021,China;Department of Neurobiology,Xuanwu Hospital,Capital Medical University,Beijing 100053,China)
出处
《中华行为医学与脑科学杂志》
CAS
CSCD
北大核心
2020年第5期406-412,共7页
Chinese Journal of Behavioral Medicine and Brain Science
基金
国家重点研发计划项目(2018YFA0108500)
国家自然科学基金项目(31472056)。
关键词
帕金森病
食蟹猴
多巴丝肼
多奈哌齐
行为学
认知障碍
Parkinson's disease
Cynomolgus monkey
Benserazide-levodopa
Donepezil
Behavior
Cognitive impairment
作者简介
通信作者:岳峰,Email:fyuee@hotmail.com。
