Amelioration of non-motor dysfunctions after transplantation of human dopamine neurons in a model of Parkinson's disease.
Amelioration of non-motor dysfunctions after transplantation of human dopamine neurons in a model of Parkinson's disease.
复制标题
DOI：
10.1016/j.expneurol.2016.02.003
复制
发表时间：
2016-04
影响因子：
5.3
通讯作者：
Dunnett SB
中科院分区：
文献类型：
--
作者：
Lelos MJ;Morgan RJ;Kelly CM;Torres EM;Rosser AE;Dunnett SB
帕金森氏病(PD)患者表现出认知和神经精神功能障碍，尤其是随着疾病的进展。尽管据报道，这些损害对患者生活质量的影响比任何运动功能障碍都要严重，但目前还没有能够充分针对这些非运动障碍的干预措施。利用帕金森病的啮齿动物模型，我们研究了使用人源性腹侧中脑(HVM)移植物纹状体内移植的细胞替代疗法是否可以缓解认知和神经精神以及运动功能障碍。对单侧前脑束内侧6-羟基多巴胺损毁的大鼠进行了一项复杂的可操作性任务，该任务分离了对多巴胺丧失敏感的动机、视觉空间和运动障碍。一组受损的大鼠接受了妊娠约9周的纹状体内HVM移植。移植后，大鼠接受了重复的药物诱导的旋转测试，并在对HVM组织移植物进行尸检分析之前，进行了两种版本的复杂操作任务的测试。移植后的行为测试显示，HVM移植改善了任务表现的非运动方面，特别是视觉空间功能和动机处理，以及缓解运动功能障碍。在帕金森病的动物模型中，我们报告了人类VM细胞移植同时缓解非运动和运动功能障碍的第一个证据。因此，这种干预是第一次改善帕金森病模型中长期存在的认知和神经精神症状。非运动功能障碍影响帕金森病患者的生活质量。我们测试了人类来源的胎儿多巴胺细胞是否可以改善这些缺陷。人类多巴胺细胞改善了大鼠模型中的旋转偏向和运动障碍。非运动功能障碍，特别是视觉空间和动机缺陷得到改善。这是人类多巴胺细胞改善非运动缺陷的第一个证据。
Patients suffering from Parkinson's disease (PD) display cognitive and neuropsychiatric dysfunctions, especially with disease progression. Although these impairments have been reported to impact more heavily upon a patient's quality of life than any motor dysfunctions, there are currently no interventions capable of adequately targeting these non-motor deficits. Utilizing a rodent model of PD, we investigated whether cell replacement therapy, using intrastriatal transplants of human-derived ventral mesencephalic (hVM) grafts, could alleviate cognitive and neuropsychiatric, as well as motor, dysfunctions. Rats with unilateral 6-hydroxydopamine lesions to the medial forebrain bundle were tested on a complex operant task that dissociates motivational, visuospatial and motor impairments sensitive to the loss of dopamine. A subset of lesioned rats received intrastriatal hVM grafts of ~ 9 weeks gestation. Post-graft, rats underwent repeated drug-induced rotation tests and were tested on two versions of the complex operant task, before post-mortem analysis of the hVM tissue grafts. Post-graft behavioural testing revealed that hVM grafts improved non-motor aspects of task performance, specifically visuospatial function and motivational processing, as well as alleviating motor dysfunctions. We report the first evidence of human VM cell grafts alleviating both non-motor and motor dysfunctions in an animal model of PD. This intervention, therefore, is the first to improve cognitive and neuropsychiatric symptoms long-term in a model of PD. Non-motor dysfunctions affect quality of life in Parkinson's disease. We tested whether human-derived foetal dopamine cells could improve these deficits. Human dopamine cells improved rotational bias and movement impairments in a rat model. Non-motor dysfunctions, specifically visuospatial and motivational deficits, improved. This is the first evidence of improved non-motor deficits from human dopamine cells.