Neuroprotective efficacy of P7C3 compounds in primate hippocampus

Abstract

There is a critical need for translating basic science discoveries into new therapeutics for patients suffering from difficult to treat neuropsychiatric and neurodegenerative conditions. 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. Subsequently, neuroprotective efficacy of P7C3 compounds in a broad spectrum of preclinical rodent models has also been observed. An important next step in translating this work to patients is to determine whether P7C3 compounds exhibit similar efficacy in primates. Adult male rhesus monkeys received daily oral P7C3-A20 or vehicle for 38 weeks. During weeks 2–11, monkeys received weekly injection of 5′-bromo-2-deoxyuridine (BrdU) to label newborn cells, the majority of which would normally die over the following 27 weeks. BrdU+ cells were quantified using unbiased stereology. 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. 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. 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. 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.

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

“…It has been demonstrated that P7C3 and its analogs have neuroprotective efficacy in a broad range of preclinical rodent and nonhuman primate models relying on the activation of NAMPT. 635 – 638 Therefore, the neuroprotective activity of P7C3 offers a new pharmacotherapy for age-associated ALS, Alzheimer’s disease and Parkinson’s disease. 635 , 637 , 638 SBI-797812 activates NAMPT via stabilizing the NAMPT phosphorylation at His247, enhancing the efficiency of NMN generation, providing another option to raise NAD + .…”

“… 635 – 638 Therefore, the neuroprotective activity of P7C3 offers a new pharmacotherapy for age-associated ALS, Alzheimer’s disease and Parkinson’s disease. 635 , 637 , 638 SBI-797812 activates NAMPT via stabilizing the NAMPT phosphorylation at His247, enhancing the efficiency of NMN generation, providing another option to raise NAD + . 639 Together, the NAMPT enhancers, P7C3 and SBI-797812, warrant further study for the clinical treatment of neuron related diseases.…”

P7C3-A20 treatment one year after TBI in mice repairs the blood–brain barrier, arrests chronic neurodegeneration, and restores cognition

“…Mice were then administered either vehicle (TBI-Veh, Sham-Veh) or P7C3-A20 (10 mg⋅kg −1 ⋅day −1 intraperitoneally [IP]; TBI-P7C3-A20) for 4 wk. P7C3-A20 is an aminopropyl carbazole that elevates cellular nicotinamide adenine dinucleotide, enhances survival of adult-born young hippocampal neurons, and has been shown to preserve mature neurons and improve cognition in various models of nervous system disease and injury ( 25 – 45 ). Immediately after treatment completion, cognitive function in the 15-mo-old animals was evaluated through Morris water maze (MWM) testing.…”

Adult-born neurons inhibit developmentally-born neurons in the dentate gyrus

“…We therefore adopted a neurogenic approach that is more translatable to human conditions, and provide support for the emerging role of neurogenesis in DG inhibition. Neurogenic therapies, such as exercise, MEM or other compounds such as P7C3 (which has recently been validated in nonhuman primates [71]) could therefore be viable approaches for treating cognitive and mental health disorders that are associated with altered excitationinhibition balance in the DG.…”