Hippocampal neurogenesis represents a promising target for discovery of novel therapeutic agents for disorders of mood and cognition. All known antidepressants stimulate hippocampal neurogenesis and impaired neurogenesis may be etiologic in depression and schizophrenia. Systematic drug discovery and development (DDD) efforts have been hampered, however, by the limited throughput, precision and sensitivity of existing techniques for measuring neurogenesis in vivo (i.e., BrdU labeling and counting). To overcome these limitations, we developed a sensitive, high-throughput assay for measuring hippocampal progenitor cell proliferation and neurogenesis in vivo. Incorporation of the non-radioactive isotope, deuterium (2H), into deoxyribose moiety of DNA in proliferating progenitor cells is measured by mass spectrometry, after labeling mice with heavy water (2H2O) for 7-12 days. This assay reproducibly detects neurogenic actions of current antidepressants and identified pipeline anti-depressant agents and dose, among unknown compounds in blinded studies. Moreover, a screening initiative of 15 approved drugs resulted in discovery of two novel and patentable neurogenic agents (confirmed as class effects), representing proof-of-concept for the present proposal. The goal of this Phase I SBIR project is to discover novel neurogenic agents.
Aim 1 is to apply this assay for screening of approximately 80 in-licensed compounds for neurogenic activity, focusing on greater activity and earlier onset of action. These agents are in-licensed by KineMed from pharmaceutical partner companies and have all completed preclinical or Phase I-II clinical studies, but were halted for reasons other than toxicity. Neurogenic agents identified by this approach will be evaluated intensively for potency (dose-response) and time to onset of action and will also be tested in standard behavioral models of antidepressant activity and cognition. The most promising agents will be used for lead optimization or directly carried forward into Phase IIa clinical trials with partners, as antidepressants and/or cognitive enhancers.
In Aim 2, we will focus on neurogenic and behavioral effects of antipsychotic agents, to test the hypothesis that 'atypical' antipsychotics have effects on mood and cognition that involve enhancement of neurogenesis. The goal is to enable use of neurogenesis as a metric for preclinical evaluation of antipsychotics. In summary, these studies will use hippocampal neurogenesis for systematic pathway-based DDD in psychiatric and cognitive disorders. Disorders of mood and thought processes including depression, schizophrenia, and Alzheimer's disease, are common and debilitating. A remarkable and hopeful biologic finding is that an impaired capacity to produce new brain cells, termed neurogenesis, may contribute to these disorders and can be improved by drug treatment. We will use a powerful new method for measuring the production of new brain cells as a way to discover new drugs, and we will then test the effectiveness of these drugs on depression and memory. ? ? ?
