PATHOGENESIS AND TREATMENT OF NEURODEGENERATIVE DISEASE

该项目的长期目标是将BASIC 神经科学研究有效的姑息性和保护性干预措施 用于影响运动和认知功能的神经退行性疾病。 理解反应发病机制的研究进展 左旋多巴治疗帕金森病的变化 继续。在患有这种疾病的患者中，阿朴吗啡是一种直接的多巴胺 受体激动剂，被发现复制了潜在的反应变化 左旋多巴引起的运动波动和舞蹈性运动障碍 挑战，从而为早期动物模型提供了强有力的临床支持 观察到突触后对多巴胺的二次修饰 系统解释了这种致残综合症的出现。去年我们 报道称，NMDA受体拮抗剂可改善大鼠运动并发症 MPTP损害灵长类动物以及6-羟基多巴胺损害的大鼠。现在 我们发现，与某些类型的药物联合治疗也可以阻断 这些反应改变的外观。以往的啮齿动物模型研究 提示这些谷氨酸拮抗剂的作用主要是通过 纹状体中棘神经元上的NMDA受体。现在看来， CAMP依赖蛋白激酶(PKA)信号通路的激活 与共表达的多巴胺能受体相连参与NMDA 受体上调；目前的结果表明酪氨酸增加 NR1和NR2B亚基上的磷酸化是这一点的基础 功能变化。N-甲基-D-天冬氨酸受体超敏反应在脑损伤中的作用 帕金森氏症患者的运动并发症得到进一步支持 一种治疗方法，现在发现了一种可控的 研究表明，右美沙芬和金刚烷胺可以减少这些 在不影响左旋多巴抗肿瘤作用的情况下发生医源性反应改变 帕金森氏症疗效。 纹状体棘神经元凋亡机制的研究也已开始。 确定新型药物干预的潜在靶点。至 表征兴奋性毒性神经元的分子机制 死亡后，纹状体转录因子结合活性的变化 在注射喹啉酸后测量。NFkB结合迅速增加 随之而来的是凋亡性圣痕的出现。这两个变化都是 环己亚胺和NFkB选择性阻断剂NFkB SN50的抑制作用 核移位。NFkB参与了兴奋性毒素的诱导 纹状体神经元的凋亡破坏促使人们探索 选择性抑制该因子的方法。相关研究 已经发现，刺激代谢性受体可以增加红藻氨酸 酸诱导的BUT减弱NMDA诱导的细胞凋亡样死亡 神经元。在MPTP受损的灵长类动物中，强大的神经保护一直是 用谷氨酸拮抗剂但不用自由基获得 清道夫。

The long-term goal of this project is to translate results of basic neuroscience research into useful palliative and protective interventions for neurodegenerative disorders affecting motor and cognitive function. Progress towards understanding the pathogenesis of the response alterations complicating levodopa treatment of Parkinson's disease has continued. In patients with this disorder, apomorphine, a direct dopamine receptor agonist, was found to replicate the response changes underlying motor fluctuations and choreiform dyskinesias elicited by levodopa challenge, thus providing strong clinical support for earlier animal model observations that secondary modifications postsynaptic to the dopamine system account for the appearance of this disabling syndrome. Last year we reported that NMDA receptor antagonists ameliorate motor complications in MPTP lesioned primates as well as in 6-hydroxydopamine-lesioned rats. Now we find that co-therapy with certain drugs of this type can also block the appearance of these response alterations. Previous rodent model studies suggested that these glutamate antagonist effects were primarily mediated by NMDA receptors on striatal medium spiny neurons. It now appears that activation of cAMP-dependent protein kinase (PKA) signaling pathways linked to co-expressed dopaminergic receptors participates in the NMDA receptor up-regulation; current results suggest that increased tyrosine phosphorylation on both the NR1 and NR2B subunits underlies this functional change. The contribution of NMDA receptor supersensitivity to motor complications in parkinsonian patients has been further supported and an approach to treatment now discovered by findings of controlled studies showing that dextromethorphan and amantadine diminish these iatrogenic response alterations without compromising levodopa's anti- parkinsonian efficacy. Studies of apoptotic mechanisms in striatal spiny neurons have also begun to identify potential targets for novel pharmaceutical intervention. To characterize molecular mechanisms contributing to excitotoxic neuronal death, changes in striatal transcription factor binding activity were measured after quinolinic acid infusion. NFkB binding rapidly increased followed by the appearance of apoptotic stigmata. Both changes were inhibited by cycloheximide and by NFkB SN50, a selective blocker of NFkB nuclear translocation. NFkB involvement in the excitotoxin-induced apoptotic destruction of striatal neurons has prompted exploration of approaches to the selective inhibition of this factor. Related studies have found that metabotropic receptor stimulation augments the kainic acid-induced but attenuates the NMDA-induced apoptotic-like death of these neurons. In MPTP lesioned primates, robust neuroprotection has been obtained with a glutamate antagonist but not with a free radical scavenger.