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.

Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

“…Clearly, the mechanisms mediating the effect of P7C3 on cognition might involve biological processes beyond hippocampal neurogenesis that could regulate broader aspects of brain plasticity. In follow-up studies, modified and more potent analogues of P7C3 demonstrated that the compound class exhibits neuroprotective effect in models of Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, and age-related cognitive decline (MacMillan et al 2011;Blaya et al 2014;Walker et al 2014). Derivatives appended with immobilizing moieties may reveal the protein targets of the P7C3 class of neuroprotective compounds.…”

Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors

“…Tangential support for this hypothesis includes a study in which deletion of neurofibromin 1 from adult-born cells increased levels of adult neurogenesis and had an antidepressant-like effect on behavior; however, this manipulation not only increased the number of adultborn neurons, but also affected these cells in other ways, such as by activating ERK signaling (Li et al, 2012). More recently, the P7C3 compound has been shown to increase adult neurogenesis and has an antidepressant-like effect on social interaction behavior following social defeat; however, P7C3 likely exerts its effects through multiple biological processes including, but not limited to, neurogenesis (Walker et al, 2014;Wang et al, 2014;Yin et al, 2014).…”

β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

“…Following the unique posttranslational addition of an acyl group by ghrelin O-acyltransferase (GOAT), ghrelin can bind and activate the G protein-coupled growth hormone secretagogue receptor (GHSR), which is the only known ghrelin receptor (1)(2)(3). It is via CNS and/or peripheral GHSRs that ghrelin influences growth hormone (GH) secretion, mood, gastrointestinal motility, hippocampal neurogenesis, and many other processes (4)(5)(6)(7)(8)(9)(10). Actions of unmodified ghrelin (desacyl-ghrelin), the modes thereof, and the potential significance of the acyl-ghrelin/ desacyl-ghrelin ratio are less well described (4).…”