The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis

Walker, A K; Rivera, P D; Wang, Q; Chuang, J-C; Tran, S; Osborne-Lawrence, S; Estill, S J; Starwalt, R; Huntington, P; Morlock, L; Naidoo, J; Williams, N S; Ready, J M; Eisch, A J; Pieper, A A; Zigman, J M

doi:10.1038/mp.2014.34

Cited by 162Neurogenesis and neuroplasticity mechanismsTreatment of Major DepressionStress Responses and Cortisol

The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis

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Walker, A K, Rivera, P D, Wang, Q, Chuang, J-C, Tran, S, Osborne-Lawrence, S, Estill, S J, Starwalt, R +8 more·2015·Molecular Psychiatry

DOI 10.1038/mp.2014.34PMC PMC4206684

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Abstract

Augmenting hippocampal neurogenesis represents a potential new strategy for treating depression. Here we test this possibility by comparing hippocampal neurogenesis in depression-prone ghrelin receptor (Ghsr)-null mice to that in wild-type littermates and by determining the antidepressant efficacy of the P7C3 class of neuroprotective compounds. Exposure of Ghsr-null mice to chronic social defeat stress (CSDS) elicits more severe depressive-like behavior than in CSDS-exposed wild-type littermates, and exposure of Ghsr-null mice to 60% caloric restriction fails to elicit antidepressant-like behavior. CSDS resulted in more severely reduced cell proliferation and survival in the ventral dentate gyrus (DG) subgranular zone of Ghsr-null mice than in that of wild-type littermates. Also, caloric restriction increased apoptosis of DG subgranular zone cells in Ghsr-null mice, although it had the opposite effect in wild-type littermates. Systemic treatment with P7C3 during CSDS increased survival of proliferating DG cells, which ultimately developed into mature (NeuN+) neurons. Notably, P7C3 exerted a potent antidepressant-like effect in Ghsr-null mice exposed to either CSDS or caloric restriction, while the more highly active analog P7C3-A20 also exerted an antidepressant-like effect in wild-type littermates. Focal ablation of hippocampal stem cells with radiation eliminated this antidepressant effect, further attributing the P7C3 class antidepressant effect to its neuroprotective properties and resultant augmentation of hippocampal neurogenesis. Finally, P7C3-A20 demonstrated greater proneurogenic efficacy than a wide spectrum of currently marketed antidepressant drugs. Taken together, our data confirm the role of aberrant hippocampal neurogenesis in the etiology of depression and suggest that the neuroprotective P7C3-compounds represent a novel strategy for treating patients with this disease.

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Elevated ghrelin levels exert anti-inflammatory effects, metabolic regulation, and promote cognitive enhancement.
“This is an interesting finding, as elevated ghrelin levels are known to exert anti-inflammatory effects, metabolic regulation, and promote cognitive enhancement [20, 45, 47].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [47]
The Introduction (page not provided) describes ghrelin’s role in feeding and metabolic responses to stress, and says ghrelin signaling enhances memory retention. It does not state that elevated ghrelin levels exert anti-inflammatory effects; a References entry mentions a study of blocked microglial activation, but that does not establish the broader claim. (LLM, conf=0.84)
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The current state of the neurogenic theory of depression and anxiety
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Adult Neurogenesis and Psychiatric DisordersPreprint
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Current and future therapeutic strategies for Alzheimer’s disease: an overview of drug development bottlenecks
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Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease
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Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis
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From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms
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P7C3 Neuroprotective Chemicals Block Axonal Degeneration and Preserve Function after Traumatic Brain Injury
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Short-term calorie restriction enhances adult hippocampal neurogenesis and remote fear memory in a Ghsr-dependent manner
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Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment
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Ghrelin in psychiatric disorders – A review
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Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive
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Faster, better, stronger: Towards new antidepressant therapeutic strategies
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The orexigenic hormone acyl-ghrelin increases adult hippocampal neurogenesis and enhances pattern separation
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Early Detection of Subclinical Visual Damage After Blast-Mediated TBI Enables Prevention of Chronic Visual Deficit by Treatment With P7C3-S243
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P7C3-A20 treatment one year after TBI in mice repairs the blood–brain barrier, arrests chronic neurodegeneration, and restores cognition
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NAMPT as a Therapeutic Target against Stroke
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Exercise for Mental Well-Being: Exploring Neurobiological Advances and Intervention Effects in Depression
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Stress and obesity: The ghrelin connection
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(−)-P7C3-S243 Protects a Rat Model of Alzheimer’s Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia
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The protective effects of Ghrelin/GHSR on hippocampal neurogenesis in CUMS mice.
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Too much death can kill you: inhibiting intrinsic apoptosis to treat disease
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Discovery of a Neuroprotective Chemical, ( S )- N -(3-(3,6-Dibromo-9 H -carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(−)-P7C3-S243], with Improved Druglike Properties
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Acute Axonal Degeneration Drives Development of Cognitive, Motor, and Visual Deficits after Blast-Mediated Traumatic Brain Injury in Mice
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Effects of indole-3-carbinol on clonidine-induced neurotoxicity in rats: Impact on oxidative stress, inflammation, apoptosis and monoamine levels
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The neuroprotective compound P7C3-A20 promotes neurogenesis and improves cognitive function after ischemic stroke
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Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers
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TRPV1 Regulates Stress Responses through HDAC2
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The Neuropsychiatric Disease-Associated Genecacna1cMediates Survival of Young Hippocampal Neurons
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Whole-Body Exposure to28Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term
Whoolery, C. W., Walker, A. K., Richardson, D. R., Lucero, M. J., Reynolds, R. P., Beddow, D. H., Clark, K. L., Shih, H.-Y., LeBlanc, J. A., Cole, M. G., et al. (2017) · Radiation Research · doi:10.1667/rr14797.1 · Cited by 57 · see citing works
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Ghrelin-Mediated Hippocampal Neurogenesis: Implications for Health and Disease
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Ghrelin exhibited antidepressant and anxiolytic effect via the p38-MAPK signaling pathway in hippocampus
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β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals
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Pharmacologic rescue of motor and sensory function by the neuroprotective compound P7C3 following neonatal nerve injury
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“A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes”
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Protective efficacy of P7C3-S243 in the 6-hydroxydopamine model of Parkinson's disease
Jesús‐Cortés, H. D., Miller, A., Britt, J. K., DeMarco, A. J., Jesús-Cortés, M. D., Stuebing, E., Naidoo, J., Vázquez‐Rosa, E., Morlock, L., Williams, N. S., et al. (2015) · npj Parkinson s Disease · doi:10.1038/npjparkd.2015.10 · Cited by 50 · see citing works
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Neuroprotective efficacy of P7C3 compounds in primate hippocampus
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Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice
Yun, S., Donovan, M. H., Ross, M. N., Richardson, D. R., Reister, R., Farnbauch, L. A., Fischer, S. J., Riethmacher, D., Gershenfeld, H. K., Lagace, D. C., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147256 · Cited by 50 · see citing works
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Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease
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“In concert, a study in depression-prone GHS-R1α mice revealed that the deletion of GHS-R1α exacerbated neuronal loss in response to chronic social defeat stress and diminished the proliferation of progenitor cells in the ventral DG (Walker et al., 2015).”
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Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process
Khaidizar, F. D., Bessho, Y., & Nakahata, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073709 · Cited by 48 · see citing works
Neuronal PAS domain proteins 1 and 3 are master regulators of neuropsychiatric risk genes
Michaelson, J. J., Shin, M.-K., Koh, J.-Y., Brueggeman, L., Zhang, A., Katzman, A., McDaniel, L., Fang, M., Pufall, M., & Pieper, A. A. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.03.021 · Cited by 47 · see citing works
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Adult Neurogenesis and Antidepressant Treatment: The Surprise Finding by Ron Duman and the Field 20 Years Later
Malberg, J. E., Hen, R., & Madsen, T. M. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.01.010 · Cited by 46 · see citing works
Neurogenic hypothesis of positive psychology in stress-induced depression: Adult hippocampal neurogenesis, neuroinflammation, and stress resilience
Wu, Z., Xiao, L., Wang, H., & Wang, G. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107653 · Cited by 46 · see citing works
Des-Acyl Ghrelin and Ghrelin O-Acyltransferase Regulate Hypothalamic-Pituitary-Adrenal Axis Activation and Anxiety in Response to Acute Stress
Stark, R., dos Santos, V. V., Geenen, B., Cabral, A., Dinan, T., Bayliss, J. A., Lockie, S. H., Reichenbach, A., Lemus, M. B., Perelló, M., et al. (2016) · Endocrinology · doi:10.1210/en.2016-1306 · Cited by 45 · see citing works
Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury
Sridharan, P. S., Koh, Y., Miller, E., Hu, D., Chakraborty, S., Tripathi, S. J., Kee, T. R., Chaubey, K., Vázquez‐Rosa, E., Barker, S., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101715 · Cited by 44 · see citing works
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Neuroprotective Efficacy of an Aminopropyl Carbazole Derivative P7C3‐A20 in Ischemic Stroke
Wang, S., Xu, T., Wang, X., Guan, Y., Zhang, S.-L., Wang, P., & Miao, C. (2016) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12576 · Cited by 44 · see citing works
Adult neurogenesis in the mouse dentate gyrus protects the hippocampus from neuronal injury following severe seizures
Jain, S. S., LaFrancois, J. J., Botterill, J. J., Alcantara‐Gonzalez, D., & Scharfman, H. E. (2019) · Hippocampus · doi:10.1002/hipo.23062 · Cited by 43 · see citing works
Recent advances in the crosstalk between the brain-derived neurotrophic factor and glucocorticoids
Tsimpolis, A., Kalafatakis, K., & Charalampopoulos, I. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1362573 · Cited by 43 · see citing works
The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders
Fritz, E. M., Singewald, N., & Bundel, D. D. (2020) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.594484 · Cited by 42 · see citing works
P7C3‐A20 alleviates fatty liver by shaping gut microbiota and inducing FGF21/FGF1, via the AMP‐activated protein kinase/CREB regulated transcription coactivator 2 pathway
Hua, X., Sun, D., Zhang, W., Fu, J., Tong, J., Sun, S., Zeng, F., Ouyang, S., Zhang, G., Wang, S., et al. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15008 · Cited by 40 · see citing works
P7C3 inhibits GSK3β activation to protect dopaminergic neurons against neurotoxin-induced cell death in vitro and in vivo
Gu, C., Zhang, Y., Hu, Q., Wu, J., Ren, H., Liu, C., & Wang, G. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.250 · Cited by 39 · see citing works
Neurotherapeutic capacity of P7C3 agents for the treatment of Traumatic Brain Injury
Blaya, M. O., Wasserman, J. M., Pieper, A. A., Sick, T. J., Bramlett, H. M., & Dietrich, W. D. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.09.024 · Cited by 37 · see citing works
Self-citation
Antidepressant-like effects of acupuncture involved the ERK signaling pathway in rats
Zhang, X., Song, Y., Bao, T., Yu, M., Xu, M., Guo, Y., Wang, Y., Zhang, C., & Zhao, B. (2016) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-016-1356-x · Cited by 37 · see citing works
β1-adrenergic receptors mediate plasma acyl-ghrelin elevation and depressive-like behavior induced by chronic psychosocial stress
Gupta, D., Chuang, J.-C., Mani, B. K., Shankar, K., Rodriguez, J. A., Osborne-Lawrence, S. L., Metzger, N. P., & Zigman, J. M. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0334-7 · Cited by 37 · see citing works
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Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age
McAvoy, K., Russo, C., Kim, S., Rankin, G., & Sahay, A. (2015) · Hippocampus · doi:10.1002/hipo.22464 · Cited by 36 · see citing works
Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice
Ito, N., Hirose, E., Ishida, T., Hori, A., Nagai, T., Kobayashi, Y., Kiyohara, H., Oikawa, T., Hanawa, T., & Odaguchi, H. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0876-8 · Cited by 36 · see citing works
Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans
Hornsby, A. K. E., Buntwal, L., Carisi, M. C., Santos, V. V., Johnston, F., Roberts, L. D., Sassi, M., Mequinion, M., Stark, R., Reichenbach, A., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100120 · Cited by 35 · see citing works
“4 Cell Reports Medicine 1, 100120, October 20, 2020 (A and B) Peripheral administration of UAG or genetic ablation of GOAT reduces the number of c-Fos+ neurons in the mouse DG. Statistical analysis was performed by 2-way ANOVA followed by Holm-Sidak post hoc comparisons.”
BackgroundInfluential
Targeting Nicotinamide Phosphoribosyltransferase as a Potential Therapeutic Strategy to Restore Adult Neurogenesis
Wang, S., Xu, T., Li, W., & Miao, C. (2016) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12539 · Cited by 35 · see citing works
Leptin and ghrelin dynamics: unraveling their influence on food intake, energy balance, and the pathophysiology of type 2 diabetes mellitus
Vijayashankar, U., Ramashetty, R., Rajeshekara, M., Vishwanath, N., Yadav, A. K., Prashant, A., & Lokeshwaraiah, R. (2024) · Journal of Diabetes and Metabolic Disorders · doi:10.1007/s40200-024-01418-2 · Cited by 35 · see citing works
P7C3 Inhibits LPS-Induced Microglial Activation to Protect Dopaminergic Neurons Against Inflammatory Factor-Induced Cell Death in vitro and in vivo
Gu, C., Hu, Q., Wu, J., Mu, C., Ren, H., Liu, C., & Wang, G. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00400 · Cited by 34 · see citing works
The Ghrelin-AgRP Neuron Nexus in Anorexia Nervosa: Implications for Metabolic and Behavioral Adaptations
Méquinion, M., Foldi, C. J., & Andrews, Z. B. (2020) · Frontiers in Nutrition · doi:10.3389/fnut.2019.00190 · Cited by 34 · see citing works
NAMPT and NAMPT-controlled NAD Metabolism in Vascular Repair
Wang, P., Li, W., Liu, J., & Miao, C. (2015) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000332 · Cited by 32 · see citing works
56Fe Particle Exposure Results in a Long-Lasting Increase in a Cellular Index of Genomic Instability and Transiently Suppresses Adult Hippocampal Neurogenesis in Vivo
DeCarolis, N. A., Rivera, P. D., Ahn, F., Amaral, W. Z., Leblanc, J. A., Malhotra, S., Shih, H.-Y., Petrik, D., Melvin, N., Chen, B. P. C., et al. (2014) · Life sciences and space research · doi:10.1016/j.lssr.2014.06.004 · Cited by 36 · see citing works
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Examining immune-inflammatory mechanisms of probiotic supplementation in depression: secondary findings from a randomized clinical trial
Sempach, L., Doll, J. P. K., Limbach, V., Marzetta, F., Schaub, A.-C., Schneider, E., Kettelhack, C., Mählmann, L., Schweinfurth, N., Ibberson, M. R., et al. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03030-7 · Cited by 33 · see citing works
Insights into the Biology and Therapeutic Applications of Neural Stem Cells
Harris, L., Zalucki, O. H., Piper, M., & Heng, J. I. (2016) · Stem Cells International · doi:10.1155/2016/9745315 · Cited by 26 · see citing works
NPAS3 Regulates Transcription and Expression of VGF: Implications for Neurogenesis and Psychiatric Disorders
Yang, D., Zhang, W., Padhiar, A. A., Yao, Y., Shi, Y., Zheng, T., Davis, K., Zhang, Y., Huang, M., Li, Y., et al. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00109 · Cited by 26 · see citing works
Chronic P7C3 treatment restores hippocampal neurogenesis
Latchney, S. E., Jaramillo, T. C., Rivera, P. D., Eisch, A. J., & Powell, C. M. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.02.008 · Cited by 26 · see citing works
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Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis
Smart, D. D., Garcia-Glaessner, A., Palmieri, D., Wong‐Goodrich, S. J. E., Kramp, T. R., Gril, B., Shukla, S., Lyle, L. T., Hua, E., Cameron, H. A., et al. (2015) · Clinical & Experimental Metastasis · doi:10.1007/s10585-015-9739-9 · Cited by 26 · see citing works
Neuroregeneration Versus Neurodegeneration: Toward a Paradigm Shift in Alzheimer'S Disease Drug Discovery
Uliassi, E., Gandini, A., Perone, R. C., & Bolognesi, M. L. (2017) · Future Medicinal Chemistry · doi:10.4155/fmc-2017-0038 · Cited by 24 · see citing works
Image‐guided cranial irradiation‐induced ablation of dentate gyrus neurogenesis impairs extinction of recent morphine reward memories
Rivera, P. D., Simmons, S. J., Reynolds, R. P., Just, A. L., Birnbaum, S. G., & Eisch, A. J. (2019) · Hippocampus · doi:10.1002/hipo.23071 · Cited by 24 · see citing works
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Beneficial Effects of Delayed P7C3-A20 Treatment After Transient MCAO in Rats
Loris, Z. B., Hynton, J. R., Pieper, A. A., & Dietrich, W. D. (2017) · Translational Stroke Research · doi:10.1007/s12975-017-0565-z · Cited by 23 · see citing works
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Pharmacological manipulation of the ghrelin system and alcohol hangover symptoms in heavy drinking individuals: Is there a link?
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Authors: Walker, A. K., Rivera, P. D., Wang, Q., Chuang, J.-C., Tran, S., Osborne-Lawrence, S., Estill, S. J., Starwalt, R., Huntington, P., Morlock, L., Naidoo, J., Williams, N. S., Ready, J. M., Eisch, A. J., Pieper, A. A., & Zigman, J. M.
Affiliations: The University of Texas Southwestern Medical Center (US)
University of Iowa (US)
ORCID: Rivera, P D
Wang, Q
Osborne-Lawrence, S
Estill, S J
Starwalt, R
Naidoo, J
Ready, J M
Eisch, A J
Pieper, A A
Zigman, J M
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2014-04-22
Volume: 20
Issue: 4
Pages: 500-508
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/mp.2014.34
PMC: PMC4206684
OpenAlex: W2169945211
Cited by: 161
References: 75
Citations by year: 2026: 11 · 2025: 10 · 2024: 11 · 2023: 9 · 2022: 8 · 2021: 10 · 2020: 11 · 2019: 13 · 2018: 11 · 2017: 18 · 2016: 16 · 2015: 18 · 2014: 14
FWCI: 7.77
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Molecular Psychiatry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Veterans Affairs (I01 BX002444)
Welch Foundation
National Institute of Mental Health (R01MH087986, R01MH085298)
National Institute on Drug Abuse (DA023555, K02DA023555, R01DA024680, DA016765, T32DA007290, R01DA016765)
Topics: Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: neuroprotective compounds, antidepressant efficacy, hippocampal neurogenesis, depression, growth hormone secretagogue receptor, chronic social defeat stress, caloric restriction, dentate gyrus subgranular zone, cell proliferation, apoptosis, hippocampal stem cells
MeSH terms: Animals, Antidepressive Agents, Behavioral Symptoms, Carbazoles, Disease Models, Animal, Hippocampus, Male, Mice, Inbred C57BL, Neurons, Phosphopyruvate Hydratase, Swimming, Time Factors, Cranial Irradiation, Neuroprotective Agents, Ki-67 Antigen, Caloric Restriction, Cell Proliferation, Mice, Receptors, Ghrelin, Neurogenesis

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The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis

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