Development and Testing of a Novel Neuroprotective Drug

描述(由申请人提供)：在神经系统疾病中，迫切需要预防神经细胞死亡的治疗方法。例如阿尔茨海默氏症和帕金森氏症，以及ALS和亨廷顿病等不太常见的疾病。此外，还有同样难治的情况，如中风和非AD记忆力丧失。五年前，我们实验室发现了一种新的小型有机药效团，可以防止多种神经细胞死亡组织培养范例中的细胞死亡，包括淀粉样毒性、神经营养因子撤除、兴奋性毒性、葡萄糖饥饿和氧化应激。这种化合物的作用似乎是神经特异性的，因为它不能阻止由肿瘤坏死因子-α或星形孢子素引起的成纤维细胞的凋亡死亡。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有效性，然后在几种与年龄相关的神经疾病的动物模型中测试这些改进版本的化合物，包括AD、亨廷顿氏症和ALS。此外，由于该化合物在压力条件下保持CREB水平升高，因此将在小鼠记忆模型中研究其有效性。这些研究的结果将决定这种新化合物的治疗潜力。

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.