title: The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis.
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.
authors.affiliation: 1] Department of Internal Medicine, Divisions of Hypothalamic Research and Endocrinology & Metabolism, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Walker
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Rivera
authors.affiliation: 1] Department of Internal Medicine, Divisions of Hypothalamic Research and Endocrinology & Metabolism, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 1] Department of Internal Medicine, Divisions of Hypothalamic Research and Endocrinology & Metabolism, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J-C
authors.initials: JC
authors.lastname: Chuang
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tran
authors.affiliation: 1] Department of Internal Medicine, Divisions of Hypothalamic Research and Endocrinology & Metabolism, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Osborne-Lawrence
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Estill
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Starwalt
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Huntington
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Morlock
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Ready
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Eisch
authors.affiliation: Departments of Psychiatry and Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Pieper
authors.affiliation: 1] Department of Internal Medicine, Divisions of Hypothalamic Research and Endocrinology & Metabolism, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Zigman
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001526:Behavioral Symptoms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D031204:Caloric Restriction; D002227:Carbazoles / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D016371:Cranial Irradiation; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects / Q000528:radiation effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000172:deficiency / Q000235:genetics; D013550:Swimming / Q000523:psychology; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D002227:Carbazoles; D019394:Ki-67 Antigen; D018696:Neuroprotective Agents; C552520:P7C3 compound; D054440:Receptors, Ghrelin; D010751:Phosphopyruvate Hydratase
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