PATHOGENESIS AND TREATMENT OF NEURODEGENERATIVE DISEASE

该项目的长期目标是将基础研究成果转化为 神经科学研究，以有效的姑息和保护干预措施 治疗影响运动和认知功能的神经退行性疾病 在了解反应的发病机制方面取得的进展 左旋多巴治疗帕金森病的复杂变化 持续期间内的在患有这种疾病的患者中，阿扑吗啡，一种直接的多巴胺 受体激动剂，被发现复制反应的变化， 左旋多巴引起的运动波动和舞蹈样运动障碍 挑战，从而为早期动物模型提供了强有力的临床支持 观察到多巴胺突触后的次级修饰 系统解释了这种致残综合症的出现。去年我们 报道，NMDA受体拮抗剂改善运动并发症， MPTP损伤的灵长类动物以及6-羟基多巴胺损伤的大鼠。现在 我们发现，与这种类型的某些药物的共同治疗也可以阻断 这些反应的变化。先前的啮齿动物模型研究 表明这些谷氨酸拮抗剂的作用主要是由 纹状体中型多刺神经元上的NMDA受体。现在看来 cAMP依赖性蛋白激酶（PKA）信号通路的激活 与共表达的多巴胺能受体相关，参与NMDA 受体上调;目前的结果表明，增加酪氨酸 NR 1和NR 2B亚基上的磷酸化是这一点的基础。 功能改变。NMDA受体超敏性对 帕金森病患者的运动并发症得到了进一步的支持， 而现在的治疗方法是通过控制 研究表明，美沙芬和金刚烷胺减少这些 医源性反应改变，而不影响左旋多巴的抗- 帕金森疗效 对纹状体棘状神经元凋亡机制的研究也已开始 以确定新型药物干预的潜在靶点。到 表征有助于兴奋性毒性神经元的分子机制 死亡，纹状体转录因子结合活性的变化， 在喹啉酸输注后测量。NFkB结合迅速增加 随后出现凋亡性气门。这两个变化是 受放线菌酮和NFkB选择性阻断剂SN 50抑制 核转位NFkB参与兴奋性毒素诱导的 纹状体神经元的凋亡性破坏促进了对 选择性抑制该因子的方法。相关研究 已经发现代谢型受体刺激增加红藻氨酸 酸诱导的，但减弱NMDA诱导的这些 神经元在MPTP受损的灵长类动物中， 用谷氨酸拮抗剂而不是用自由基获得 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.