In Vivo Efficacy of New Neuroprotective Drugs

描述（由申请人提供）：神经细胞死亡引起的神经系统疾病越来越受到关注，因为它们与我们日益老龄化的人口有关。目前，即使有，也很少有药物能够穿过血脑屏障，防止与阿尔茨海默氏症等疾病相关的神经细胞死亡。在R21基金的支持下，在过去的几年里，我们的实验室合成了两种新的小有机化合物，可以在各种毒性应激细胞培养试验中防止神经细胞死亡。这些化合物具有类似于脑源性神经营养因子的活性，可防止与营养因子戒断、兴奋性毒性、葡萄糖饥饿、氧化应激以及细胞内和细胞外淀粉样蛋白毒性相关的神经细胞死亡。我们在这一组中最好的铅在一些检测中EC50低于10纳摩尔，并且还能刺激海马切片制剂中的LTP。另一种先导化合物被证明除了具有神经保护作用外，还能增强老鼠的记忆。来自两个外部实验室和我们自己实验室的初步实验表明，我们的两种化合物都可能具有减少AD动物模型认知缺陷或A21-42积累的能力。其中一种化合物对兔缺血模型也有保护作用。虽然之前的R21支持化学和一些动物研究（记忆和PK研究），但既没有足够的时间也没有足够的资金来充分探索这些化合物在神经退行性疾病动物模型中的功效。为了解决这一重要问题，我们将在两种与阿尔茨海默氏症相关的神经系统疾病动物模型中测试这两种化合物，一种是AD人APP/PS1转基因系，另一种是表现tau病理的小鼠系。这项工作将使我们能够确定这种新型药物的潜力，用于进一步临床开发治疗阿尔茨海默病。如果一种或两种药物在一种或多种动物模型中取得成功，我们将申请U01拨款，以推动它们获得IND批准和临床应用。

DESCRIPTION (provided by applicant): Diseases of the nervous system caused by nerve cell death represent a growing concern because of their association with our increasingly older population. There are currently few, if any, drugs that are able to cross the blood-brain barrier and prevent nerve cell death associated with diseases like Alzheimer's. With the support of a R21 grant, over the past few years our laboratory has synthesized two novel small organic compounds that prevent nerve cell death in a wide variety of toxic stress cell culture assays. These compounds have an activity similar to brain derived neurotrophic factor and prevent nerve cell death associated with trophic factor withdrawal, excitotoxicity, glucose starvation, oxidative stress, and both intra- and extra-cellular amyloid toxicity. Our best lead in this group has an EC50 of below 10 nanomolar in some assays and also stimulates LTP in hippocampal slice preparations. The other lead compound was shown to enhance memory in rats in addition to its neuroprotective activities. Preliminary experiments from two outside laboratories and one from our own indicate that both of our compounds may have the ability to reduce cognitive deficits or A21-42 accumulation in AD animal models. One compound also is protective in a rabbit ischemia model. While a previous R21 supported the chemistry and some animal work (memory and PK studies), there were neither sufficient time nor funds to fully explore the efficacy of these compounds in an animal model of neurodegenerative disease. To address this important issue, we will test the two compounds in two animal models of neurological disease related to Alzheimer's, an AD human APP/PS1 transgenic line and a mouse line exhibiting tau pathology. This work will allow us to determine the potential for this novel class of drugs for further clinical development for the treatment of AD. If either one or both drugs are successful in one or more of the animal models, we will then apply for a U01 grant in order to push them toward IND approval and the clinic. PUBLIC HEALTH RELEVANCE: There is a great need for drugs for the treatment of age-associated neurodegenerative diseases such as Alzheimer's disease. During the past few years our laboratory has discovered two very potent drugs that have great potential for the treatment of this disease, and we are requesting funds to test the efficacy of these drugs in two animal models of Alzheimer's. These are experiments that are required for us to move these drugs toward the clinic.