近日，来自新加坡南洋理工大学以及美国哈佛大学医学院的研究人员共同发现激活脑部一种关键蛋白能够有效阻止帕金森病的发生，同时他们还筛选出两种抗疟疾药物对与帕金森病有潜在治疗效果，相关研究结果发表在国际学术期刊PNAS 上。
帕金森病是一种发生在中枢神经系统的神经退行性疾病，能够导致病人失去对身体的控制能力，比如不能自如地移动手、胳膊和腿。帕金森病是一种非常常见的神经退行性疾病，特别是在一些老龄化程度逐渐增加的国家里，帕金森病的发病率也随之逐渐增加。目前全世界有大约1000万帕金森病人，但至今能够有效延缓或阻止帕金森病发生的治疗方法和药物仍然很少。
经过多年研究，研究人员发现激活脑部Nurr1蛋白能够保护大脑神经元产生多巴胺的能力，而多巴胺是影响机体运动能力的重要神经递质。帕金森病在发病过程中会干扰多巴胺能神经元对多巴胺的合成，逐渐造成机体失去运动控制能力。研究人员在帕金森病大鼠模型的脑部激活Nurr1，结果发现大鼠的运动能力得到改善，同时也没有表现出帕金森病的疾病症状。
随后，研究人员又对大约1000种FDA批准的药物进行了筛选，结果发现两种抗疟疾药物（Chloroquine 和 Amodiaquine）能够直接靶向Nurr1，对于帕金森病的治疗具有良好的效果。
领导该项研究的Kwang-Soo Kim教授指出，目前治疗帕金森病的金标准是通过药物或使用手术方法刺激病人大脑重新恢复多巴胺水平，但这些方法都只能在疾病早期改善病人的运动能力，不能延缓或阻止帕金森病的继续发展。而他们发现Nurr1可能是治疗帕金森病的关键靶点，同时他们也首次发现两种抗疟疾药物可能对于帕金森病治疗具有潜在效果。
研究人员希望对这两种药物进行进一步修饰设计出更好的帕金森病治疗药物，并能够将这些药物用于临床试验。
Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's disease
Chun-Hyung Kima,b,1,2, Baek-Soo Hana,c,1, Jisook Moona,d,1, Deog-Joong Kima,1, Joon Shine, Sreekanth Rajane, Quoc Toan Nguyene, Mijin Sohnc, Won-Gon Kimc, Minjoon Hana, Inhye Jeonga, Kyoung-Shim Kimc, Eun-Hye Leef, Yupeng Tug, Jacqueline L. Naffin-Olivosg, Chang-Hwan Parkf, Dagmar Ringeg, Ho Sup Yoone,h, Gregory A. Petskog,i,2, and Kwang-Soo Kim
Parkinson's disease (PD), primarily caused by selecive degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting 1-2% of the global population over the age of 65. Currently available pharmacological treatments are largely symptomatic and lose their efficacy over time with accompanying severe side effects such as dyskinesia. Thus, there is an unmet clinical need to develop mechanism-based and/or disease-modifying treatments. based on the unique dual role of the nuclear orphan receptor Nurr1 for development and maintenance of mDA neurons and their protection from inflammation-induced death, we hypothesize that Nurr1 can be a molecular target for neuroprotective therapeutic development for PD. Here we show successful identification of Nurr1 agonists sharing an identical chemical scaffold, 4-amino-7-chloroquinoline, suggesting a critical structure-activity relationship. In particular, we found that two antimalarial drugs, amodiaquine and chloroquine stimulate the transcriptional function of Nurr1 through physical interaction with its ligand binding domain (LBD). Remarkably, these compounds were able to enhance the contrasting dual functions of Nurr1 by further increasing transcriptional activation of mDA-specific genes and further enhancing transrepression of neurotoxic proinflammatory gene expression in microglia. importantly, these compounds significantly improved behavioral deficits in 6-hydroxydopamine lesioned rat model of PD without any detectable signs of dyskinesia-like behavior. These findings offer proof of principle that small molecules targeting the Nurr1 LBD can be used as a mechanism-based and neuroprotective strategy for PD.