Why Have We Failed to Achieve Neuroprotection in Parkinson's Disease?
Why Have We Failed to Achieve Neuroprotection in Parkinson's Disease?
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DOI：
10.1002/ana.21461
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发表时间：
2008-01-01
影响因子：
11.2
通讯作者：
Schapira, Anthony H. V.
中科院分区：
文献类型：
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作者：
Olanow, C. Warren;Kleburtz, Karl;Schapira, Anthony H. V.
开发一种神经保护疗法来减缓、阻止或逆转帕金森氏病(PD)的神经退行性变是这种疾病治疗中最重要的悬而未决的问题。目前的治疗方法提供了对症状的有效控制，特别是在疾病的早期阶段，但疾病的进展与“非多巴胺”特征的发展有关，如姿势不稳、摔倒和痴呆，而现有药物无法充分控制这些特征。根据病理和实验室研究，有许多有希望的候选神经保护剂，但到目前为止，还不可能确定任何药物对帕金森病具有改善疾病的作用。开发帕金森病神经保护疗法的障碍包括：(1)对于帕金森病细胞死亡的确切原因以及靶点的不确定性；(2)缺乏准确反映疾病病因、多巴胺和非多巴胺能病理模式及其慢性、进行性的帕金森病动物模型；(3)临床试验中正确剂量的确定；以及(4)临床终点的描绘，该终点是对潜在疾病的准确测量，并且不会被研究干预的潜在症状影响所混淆。在理解疾病原因、发展帕金森病动物模型和临床试验方法学方面的新进展有望加速这些问题的解决。
The development of a neuroprotective therapy that slows, stops, or reverses neurodegeneration in Parkinson's disease (PD) is the single most important unresolved issue in the management of this disorder. Current therapies provide effective control of symptoms, particularly in the early stages of the disease, but disease progression is associated with the development of "nondopaminergic" features such as postural instability, falling, and dementia that are not adequately controlled with existing medications. There are many promising candidate neuroprotective agents based on pathological and laboratory studies, but to date, it has not been possible to determine that any drug has a disease-modifying effect in PD. Obstacles to the development of a neuroprotective therapy in PD include: (1) uncertainty as to the precise cause of cell death in PD and what to, target; (2) the lack of an animal model of PD that precisely reflects the etiopathogenesis of the disease, the pattern of dopaminergic and nondopaminergic pathology, and its chronic, progressive nature; (3) determination of the correct dose to use in clinical trials; and (4) delineation of a clinical end point that is an accurate measure of the underlying disease and is not confounded by potential symptomatic effects of a study intervention. New developments in understanding the cause of the disease, in the development of animal models of PD, and in clinical trial methodology will hopefully hasten the resolution of these problems.