Development and Testing of a Novel Neuroprotective Drug

描述（由申请人提供）：对预防神经系统疾病中神经细胞死亡的治疗剂存在深刻的需求。例子包括阿尔茨海默氏病和帕金森氏病以及不太常见的疾病，如ALS和亨廷顿氏病。此外，还有同样棘手的情况，如中风和非AD记忆丧失。五年前，在我们的实验室中发现了一种新的小有机药效团，它可以防止各种神经细胞死亡组织培养范例中的细胞死亡，包括淀粉样蛋白毒性，神经营养因子戒断，兴奋性毒性，葡萄糖饥饿和氧化应激。该化合物的作用似乎是神经特异性的，因为它不阻断由TNF-α或星形孢菌素引起的成纤维细胞的凋亡性死亡。该项目的目标是使用组合和药物化学来提高这种神经保护化合物的功效，然后在几种与年龄相关的神经系统疾病的动物模型中测试这些化合物的改进版本，包括AD，亨廷顿和ALS。此外，由于该化合物在应激条件下保持CREB水平升高，因此将研究其在小鼠记忆模型中的有效性。这些研究的结果将决定这种新型化合物的治疗潜力。

DESCRIPTION (provided by applicant): There is a profound need for therapeutics that prevents nerve cell death in diseases of the nervous system. Examples include Alzheimer's and Parkinson's diseases as well as less frequent conditions such as ALS and Huntington's disease. In addition, there are equally intractable conditions such as stroke and non-AD memory loss. Five years ago a novel small organic pharmacophore was discovered in our laboratory that prevents cell death in a variety of nerve cell death tissue culture paradigms, including amyloid toxicity, neurotrophic factor withdrawal, excitotoxicity, glucose starvation, and oxidative stress. The effect of this compound appears to be nerve specific, for it does not block the apoptotic death of fibroblasts caused by TNF-alpha or staurosporine. The goals of this project are to use combinatorial and medicinal chemistry to improve the efficacy of this neuroprotective compound and then to test these improved versions of the compound in animal models of several age-associated neurological diseases, including AD, Huntington's and ALS. In addition, since the compound keeps CREB levels elevated under conditions of stress, its effectiveness in a mouse memory model will be studied. The results from these studies will determine the therapeutic potential of this novel compound.