Due to a profound lack of treatment options for neuropsychiatric disease, there is a critical need to facilitate the translation of findings from basic neuroscience to new treatments for patients. Through an in vivo screen conducted in living mice, a biologically active aminopropyl carbazole, designated P7C3, was identified with potent proneurogenic and neuroprotective properties. A multi-year structure-activity-relationship study on this chemical scaffold has enabled optimization of potency and efficacy, while minimizing real and perceived liabilities for drug development. The P7C3 class of molecules stabilizes mitochondrial membrane potential and protects neurons from cell death. Significant protective efficacy of P7C3 and it's more potent and efficacious variant, P7C3A20, has now been demonstrated in animal models of aging, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. A new challenge is to provide additional evidence that these compounds could be beneficial to the human brain. An initial step to meet this challenge is to demonstrate that the most effective of these compounds (P7C3A20) has a proneurogenic and/or protective effect in the nonhuman primate brain. Human brain disorders are defined by changes in complex human behaviors (i.e., cognition, emotion etc.), and evaluation of the therapeutic effects of neuroprotective compounds may ultimately benefit from studies in animal species that are more closely related to humans than are mice. Moreover, the literature is replete with examples of drugs that work well in mice but are not therapeutically beneficial in humans. Rhesus macaques (Macaca mulatta) provide a useful proxy for efficacy in the human, as they demonstrate many features of human physiology, anatomy and behavior. Rhesus monkeys are thus ideal for studying a variety of complex human brain disorders. However, before we can begin to explore the therapeutic potential of the P7C3 class of molecules in sophisticated nonhuman primate diseases models, we must first establish a neuroprotective role for the P7C3 class of molecules in the primate brain. Here, we propose quantification of nonhuman primate hippocampal neurogenesis as a function of exposure to P7C3A20, in order to provide a rapid, cost effective and straightforward means of assessing efficacy of neuroprotection in the rhesus monkey. Preclinical proof of principle in a nonhuman primate could provide an opportunity to translate basic science into a new therapeutic approach for patients suffering from both neuropsychiatric and neurodegenerative diseases involving diminished hippocampal neurogenesis and/or broader neurodegeneration.
This project is designed to provide additional support for a novel class of molecules demonstrating neuroprotective effects in rodent models. Preclinical proof of principle in a nonhuman primate model could provide an opportunity to translate basic science into a new therapeutic approach for patients suffering from both neuropsychiatric and neurodegenerative diseases involving diminished hippocampal neurogenesis and/or broader neurodegeneration.