PATHOGENESIS AND TREATMENT OF NEURODEGENERATIVE DISEASE

对左旋多巴引起的运动反应改变的研究 帕金森病患者发现，潜伏期到峰值的运动反应， 与症状持续时间和严重程度密切相关。结果 提示突触前补偿机制，尤其是加速突触前补偿机制， 多巴胺的周转和释放，有助于帕金森病的缺乏， 直到大多数黑质纹状体多巴胺能神经元退化。 在一项相关的实验室研究中，左旋多巴治疗帕金森病 稳定破坏超过95%的多巴胺能 神经元导致左旋多巴的持续时间进行性缩短 运动效应 这种反应的改变，类似于 帕金森病患者中出现的现象，在更少的 严重损伤的大鼠，这表明突触后变化的损失， 多巴胺神经元必须超过相对较高的阈值， 治疗产生的变化，显然是在突触后水平， 有利于快速出现磨损的波动。 随后的 临床研究证实，与长期持有的信念相反， 连接后改变，可能涉及相对可塑性 纹状体多巴胺感受系统，也占大多数缩短 在左旋多巴作用的持续时间内， 帕金森病患者中。该科以前的研究表明， 谷氨酸系统改变运动反应的能力， 多巴胺能刺激此外，我们发现，反复左旋多巴 给药下调D1多巴胺受体介导的反应， D_2受体介导的细胞凋亡上调， 运动神经对左旋多巴反应的持续时间 急性联合治疗 而非竞争性NMDA拮抗剂MK-801则完全逆转了这些变化 变化，表明NMDA受体介导的机制有助于 与长期左旋多巴治疗相关的反应变化， NMDA拮抗剂可逆转运动反应并发症 长期接受左旋多巴治疗由于皮质变性 阿尔茨海默病患者的脑神经投射是一个一致的发现， 我们评估了谷氨酸系统刺激可能 给予症状性益处。 环丝氨酸，一种间接激动剂， （NMDA）谷氨酸受体，没有一致的影响， 神经心理学结果测量，表明短期 NMDA介导的神经递质传递的增强可能无法证明 可用于该病症的对症治疗。

Studies of the altered motor responses to levodopa occurring in advanced Parkinsonian patients revealed that the latency-to-peak motor response correlated closely with symptom duration and severity. The results suggest that compensatory presynaptic mechanisms, especially accelerated dopamine turnover and release, contribute to the absence of Parkinsonian symptoms until most nigrostriatal dopaminergic neurons have degenerated. In a related laboratory investigation, levodopa treatment of Parkinsonian rats with stable destruction of more than 95% of their dopaminergic neurons leads to a progressive shortening in the duration of levodopa's motor effects. This response alteration, resembling the wearing-off phenomena that develop in Parkinsonian patients, did not occur in less severely lesioned rats, suggesting that postsynaptic changes loss of dopamine neurons must exceed a relatively high threshold before levodopa treatment produces changes, evidently at the postsynaptic level, that favor the rapid appearance of wearing-off fluctuations. A subsequent clinical study confirmed that, contrary to long-held beliefs, postjunctional alterations, possibly involving relatively plastic striatal dopaminoceptive systems, also account for most of the shortening in the duration of levodopa action that underlie wearing-off fluctuations in parkinsonian patients. Previous studies by the Section demonstrated the ability of the glutamate system to alter motor responses to dopaminergic stimulation. In addition, we found that repeated levodopa administration down-regulated D1 dopamine receptor mediated responses, up~regulated those mediated by D2 receptors, and progressively reduced the duration of the motor response to levodopa. Acute co-treatment with the noncompetitive NMDA antagonist MK-801 completely reversed all these changes, suggesting that NMDA receptor-mediated mechanisms contribute to the response changes associated with chronic levodopa treatment and that NMDA antagonists act to reverse the motor response complications attending long-term levodopa therapy. Since degeneration of cortical glutamatergic projections is a consistent finding in Alzheimer's disease, we evaluated the possibility that glutamate system stimulation might confer symptomatic benefit. Cycloserine, an indirect agonist at certain (NMDA) glutamate receptors, had no consistent effect on neuropsychological outcome measures, suggesting that short-term potentiation of NMDA-mediated glutamatergic transmission may not prove useful in the symptomatic treatment of this disorder.