In Vivo Efficacy of New Neuroprotective Drugs

点击翻译按钮获取中文摘要

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.