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

Molecular Psychiatry volume 20, pages 500–508 (2015)Cite this article

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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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Acknowledgements

These studies were made possible through funding from the NIH (1R01MH085298 and 1R01DA024680 to JMZ; T32DA007290 to AKW through AJE, DA016765 and DA023555 to AJE and 1RO1MH087986 to AAP and Steven L McKnight), institutional funds from University of Iowa Carver College of Medicine to AAP, an International Research Alliance with the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (to JMZ), the Edward N and Della C Thome Memorial Foundation (to JMR), the Welch Foundation (I-1612; to JMR), NASA (NNX12AB55G to AJE) and an unrestricted endowment provided to Steven L McKnight by an anonymous donor. We also thank Lauren Peca and Shari Birnbaum from the UTSW Medical Center Behavior Core for technical assistance.

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  1. A A Pieper and J M Zigman: The last two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Divisions of Hypothalamic Research and Endocrinology & Metabolism, University of Texas Southwestern Medical Center, Dallas, TX, USA,

    A K Walker, Q Wang, J-C Chuang, S Osborne-Lawrence & J M Zigman

  2. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA,

    A K Walker, P D Rivera, Q Wang, J-C Chuang, S Osborne-Lawrence, A J Eisch & J M Zigman

  3. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA,

    S Tran, S J Estill, R Starwalt, P Huntington, L Morlock, J Naidoo, N S Williams & J M Ready

  4. Departments of Psychiatry and Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA,

    A A Pieper

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Walker, A., Rivera, P., Wang, Q. et al. The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis. Mol Psychiatry 20, 500–508 (2015). https://doi.org/10.1038/mp.2014.34

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