P7C3

Target: Nicotinamide phosphoribosyltransferase (NAMPT)

IC50: N/A

P7C3 is an orally bioavailable proneurogenic and neuroprotective chemical which targets NAMPT enzyme [1]. NAMPT, the rate-limiting enzyme in the salvage pathway plays a critical role in the conversion of nicotinamide into nicotinamide adenine mononucleotide (NMN) and nicotinamide adenine dinucleotide (NAD) [2].

In vitro: P7C3 (1, 10, and 100 nM) preserved mitochondrial membrane potential in parallel to proneurogenic activity [1]. Administration of P7C3 (5 μM) to U2OS cells treated with doxorubicin, which induced NAD depletion, induced an increasing in intracellular NAD levels and concomitant protection from doxorubicin-mediated toxicity through the NAMPT-mediated salvage [2].

In vivo: P7C3 (5 to 40 mg/kg, oral administration) showed its proneurogenic activity through protecting newborn neurons from apoptosis. In addition, P7C3 (10 mg/kg, oral administration) enhanced hippocampal neurogenesis, preserved cognitive capacity, and prevented weight loss in terminally aged rats [1]. P7C3 (437.5 μg, twice daily via i.p. injections) treatment restored hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome [3].

References:
1.  Pieper AA, Xie S, Capota E, Estill SJ, Zhong J, Long JM, et al. Discovery of a proneurogenic, neuroprotective chemical. Cell. 2010;142(1):39-51.
2.  Wang G, Han T, Nijhawan D, Theodoropoulos P, Naidoo J, Yadavalli S, et al. P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell. 2014;158(6):1324-34.
3.  Latchney SE, Jaramillo TC, Rivera PD, Eisch AJ, Powell CM. Chronic P7C3 treatment restores hippocampal neurogenesis in the Ts65Dn mouse model of Down Syndrome [Corrected]. Neurosci Lett. 2015;591:86-92.

Neuroprotective Efficacy of an Aminopropyl Carbazole Derivative P7C3-A20 in Ischemic Stroke.[Pubmed:27333812]

CNS Neurosci Ther. 2016 Sep;22(9):782-8.

AIM: NAMPT is a novel therapeutic target of ischemic stroke. The aim of this study was to investigate the effect of a potential NAMPT activator, P7C3-A20, an aminopropyl carbazole derivative, on ischemic stroke. METHODS: In vitro study, neuron protection effect of P7C3-A20 was investigated by co-incubation with primary neurons subjected to oxygen-glucose deprivation (OGD) or oxygen-glucose deprivation/reperfusion (OGD/R) injury. In vivo experiment, P7C3-A20 was administrated in middle cerebral artery occlusion (MCAO) rats and infarct volume was examined. Lastly, the brain tissue nicotinamide adenine dinucleotide (NAD) levels were detected in P7C3-A20 treated normal or MCAO mice. RESULTS: Cell viability, morphology, and Tuj-1 staining confirmed the neuroprotective effect of P7C3-A20 in OGD or OGD/R model. P7C3-A20 administration significantly reduced cerebral infarction in MCAO rats. Moreover, brain NAD levels were elevated both in normal and MCAO mice after P7C3-A20 treatment. CONCLUSIONS: P7C3-A20 has neuroprotective effect in cerebral ischemia. The study contributes to the development of NAMPT activators against ischemic stroke and expands the horizon of the neuroprotective effect of aminopropyl carbazole chemicals.

The neuroprotective compound P7C3-A20 promotes neurogenesis and improves cognitive function after ischemic stroke.[Pubmed:28077334]

Exp Neurol. 2017 Apr;290:63-73.

Ischemic stroke is a devastating condition with few therapeutic interventions available. The neuroprotective compound P7C3-A20 inhibits mature neuronal cell death while also increasing the net magnitude of postnatal neurogenesis in models of neurodegeneration and acute injury. P7C3 compounds enhance flux of nicotinamide adenine dinucleotide (NAD) in mammalian cells, a proposed therapeutic approach to treating cerebral ischemia. The effectiveness of P7C3-A20 treatment on chronic histopathological and behavioral outcomes and neurogenesis after ischemic stroke has not previously been established. Here, a transient middle cerebral artery occlusion in rats was followed by twice daily injection of P7C3-A20 or vehicle for 7days. P7C3-A20-treated rats performed significantly better than vehicle-treated controls in sensorimotor cylinder and grid-walk tasks, and in a chronic test of spatial learning and memory. These behavioral improvements with P7C3-A20 treatment were correlated with significantly decreased cortical and hippocampal atrophy, and associated with increased neurogenesis in the subventricular zone and hippocampal dentate gyrus subgranular zone. Furthermore, cerebral ischemia significantly reduced NAD in the cortex but P7C3-A20 treatment restored NAD to sham levels. Thus, P7C3-A20 treatment mitigates neurodegeneration and augments repair in the brain after focal ischemia, which translates into chronic behavioral improvement. This suggests a new therapeutic approach of using P7C3 compounds to safely augment NAD and thereby promote two independent processes critical to protecting the brain from ischemic stroke: mature neuron survival and postnatal neurogenesis throughout the post-ischemic brain.

P7C3 Attenuates the Scopolamine-Induced Memory Impairments in C57BL/6J Mice.[Pubmed:26646000]

Neurochem Res. 2016 May;41(5):1010-9.

Memory impairment is the most common symptom in patients with Alzheimer's disease. The purpose of this study is to evaluate the memory enhancing effects of P7C3, a recently identified compound with robust proneurogenic and neuroprotective effects, on the cognitive impairment induced by scopolamine, a muscarinic acetylcholine receptor antagonist. Different behavior tests including the Y-maze, Morris water maze, and passive avoidance tests were performed to measure cognitive functions. Scopolamine significantly decreased the spontaneous alternation and step-through latency of C57BL/6J mice in Y-maze test and passive avoidance test, whereas increased the time of mice spent to find the hidden platform in Morris water maze test. Importantly, intraperitoneal administration of P7C3 effectively reversed those Scopolamine-induced cognitive impairments in C57BL/6J mice. Furthermore, P7C3 treatment significantly enhanced the level of brain-derived neurotrophic factor (BDNF) signaling pathway in the cortex and hippocampus, and the usage of selective BDNF signaling inhibitor fully blocked the anti-amnesic effects of P7C3. Therefore, these findings suggest that P7C3 could improve the scopolamine-induced learning and memory impairment possibly through activation of BDNF signaling pathway, thereby exhibiting a cognition-enhancing potential.

Protective effect of P7C3 on retinal ganglion cells from optic nerve injury.[Pubmed:28032230]

Jpn J Ophthalmol. 2017 Mar;61(2):195-203.

PURPOSE: To determine whether P7C3-A20, a proneurogenic neuroprotective agent, can protect the retinal ganglion cells (RGCs) of rats from optic nerve crushing. METHODS: The left optic nerve of 67 rats was crushed, and 5.0 mg/kg/day of P7C3-A20 (crush-P7C3) or its vehicle (crush-placebo) was injected intraperitoneally for 3 days from one day prior to the crushing. The protective effects were determined by the number of Tuj-1-stained RGCs and by the ratio of the mRNA levels of BAX/Bcl-2 on day 7. The levels of NAD and NAD-related genes were also determined. RESULTS: The density of RGCs was 2009.4 +/- 57.7 cells/mm(2) in the sham controls; it was significantly lower in the crush-placebo group at 979.7 +/- 144.3 cells/mm(2) (P < 0.0001). The neuroprotective effects of P7C3-A20 was demonstrated by the significantly higher density of 1266.0 +/- 193.1 cells/mm(2) than in the crush-placebo group (P = 0.01, Scheffe). After crushing the optic nerve the BAX/Bcl-2 ratio was higher in the optic nerves and retina, application of P7C3-A20 significantly reduced this ratio. P7C3-A20 significantly increased the NAD level in the untouched optic nerves from 1.36 +/- 0.05 to 1.59 +/- 0.10 nmol/mg protein (P = 0.02, t test). Crushing the optic nerve decreased the level to 1.27 +/- 0.21 nmol/mg protein and P7C3-A20 preserved the level at 1.43 +/- 0.10 nmol/mg protein. Crushing the optic nerve decreased the mRNA levels of Nampt and Sirt-1 in the optic nerves, while P7C3-A20 significantly restored the levels. CONCLUSIONS: P7C3-A20 can protect RGCs from optic nerve crushing possibly through preserving the NAD levels in the optic nerves.

P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage.[Pubmed:25215490]

Cell. 2014 Sep 11;158(6):1324-1334.

The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photocrosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.

Discovery of a proneurogenic, neuroprotective chemical.[Pubmed:20603013]

Cell. 2010 Jul 9;142(1):39-51.

An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3(-/-) mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging. PAPERCLIP: