The prototypical P7C3 molecule was first discovered through an unbiased in vivo screen for drug-like molecules capable of safely enhancing the net magnitude of postnatal hippocampal neurogenesis in mice 17. In rodents, the P7C3-series of compounds enhances neuronal survival under conditions that would normally lead to cell death 3. Here we present a novel, cross-species approach to advancing preclinical evaluation of the aminopropyl carbazole compound P7C3-A20 from rodents to nonhuman primates.

A rigorous preclinical research pipeline is needed to translate promising pharmacological interventions identified in animal model systems into new therapeutic interventions 16. Although questions have recently been raised regarding the extent of adult human hippocampal neurogenesis 7, 8, converging evidence from human and animal studies suggests that the ability to augment the net magnitude of postnatal neurogenesis may present a potential therapeutic intervention for multiple RDoC domains inclusive of symptoms associated with depressive and bipolar disorders, as well as for general conditions of impaired cognition 9, 10, 11, 12, 13, 14, 15. One promising avenue for central nervous system (CNS) drug development is to address alterations in the magnitude of postnatal hippocampal neurogenesis and hippocampal volume reported for many CNS disorders, including AlzheimerвЂ™s disease, schizophrenia, major depression, addiction and anxiety 5, 6. Novel therapeutics are severely lacking for patients suffering from neuropsychiatric and neurodegenerative diseases 1, 2, 3, 4. This pilot study provides evidence that P7C3-A20 safely protects neurons in nonhuman primates, suggesting that the neuroprotective efficacy of P7C3 compounds is likely to translate to humans as well. In mice, NSI-189 was shown to be pro-proliferative, and P7C3-A20 elevated the net magnitude of hippocampal neurogenesis to a greater degree than NSI-189 through its distinct mechanism of promoting neuronal survival. Orally-administered P7C3-A20 provided sustained plasma exposure, was well-tolerated, and elevated the survival of hippocampal BrdU+ cells in nonhuman primates without adverse central or peripheral tissue effects. Separately in mice, the proneurogenic efficacy of P7C3-A20 was compared to that of NSI-189, a proneurogenic drug currently in clinical trials for patients with major depression. BrdU+ cells were quantified using unbiased stereology.

During weeks 2вЂ“11, monkeys received weekly injection of 5вЂІ-bromo-2-deoxyuridine (BrdU) to label newborn cells, the majority of which would normally die over the following 27 weeks. Adult male rhesus monkeys received daily oral P7C3-A20 or vehicle for 38 weeks. An important next step in translating this work to patients is to determine whether P7C3 compounds exhibit similar efficacy in primates. Subsequently, neuroprotective efficacy of P7C3 compounds in a broad spectrum of preclinical rodent models has also been observed.

Previously, a target-agnostic in vivo screen in mice identified P7C3 aminopropyl carbazole as capable of enhancing the net magnitude of postnatal neurogenesis by protecting young neurons from death. There is a critical need for translating basic science discoveries into new therapeutics for patients suffering from difficult to treat neuropsychiatric and neurodegenerative conditions.

Stereology for dummies