NewNeural, Inc. is proposing to develop a small molecule drug (MS-818) that will significantly boost the production of new brain cells in patients who have suffered debilitating loss of brain cells and brain cell function. Our long-term strategy is to develop cell replacement therapies for patients with diseases such as stroke, Alzheimer's disease, Parkinson's disease, and age-associated memory impairment-- where loss of brain cells is associated with disease progression. We previously reported that transplanted neural stem cells display extensive migration and positional incorporation in the 24-month old rat brains, and those memory-impaired rats had significant improvement in cognitive function four weeks after transplantation. Recently, we discovered that the heterocyclic pyfimidine compound MS-818, when injected into aged rats (27 months old), induced the proliferation of neural stem cells by 7-fold. The compound also increased the proliferation of human neural stem cells in culture. Our hypothesis, supported in part by preliminary observations, is that MS-818 directly induces the proliferation of endogenous neural stem cells, which can then migrate to and repopulate the disease-affected regions of the brain. If this hypothesis is proven correct, MS-818 will offer a powerful new approach for treating patients with neurodegenerative conditions where the accelerated production of new neural cells may help improve cognitive and other neural functions. Our objective in this Phase I proposal is to confirm the feasibility of using MS-818 to promote dose-dependent neurogenesis in cell culture and animal models. We plan to test our hypothesis and accomplish our objectives with the following three specific aims: Aim 1. Confirm that MS-818 enhances neurogenesis by specifically inducing the proliferation of human NSCs in culture. Aim 2. Confirm that the MS-818-treated human neural stem cells are able to multiply and differentiate into neurons and glial cells and Aim 3. Demonstrate that MS-818 can enhance neurogenesis in aged rats in a dose-dependent manner. In Phase II, our objective will be to evaluate pharmacological effects of MS-818 on cognitive functions in animal models of disease. The extent and duration of functional improvement will be monitored and quantified, and pharmacokinetics and toxicity studies will be conducted in animals. Upon the completion of these studies, we expect to generate data to support further investigational new drug (IND)-enabling studies in animal models, in preparation for human clinical trials. [unreadable] [unreadable] [unreadable]