S 47445 Produces Antidepressant- and Anxiolytic-Like Effects through Neurogenesis Dependent and Independent Mechanisms

Abstract

Glutamatergic dysfunctions are observed in the pathophysiology of depression. The glutamatergic synapse as well as the AMPA receptor’s (AMPAR) activation may represent new potential targets for therapeutic intervention in the context of major depressive disorders. S 47445 is a novel AMPARs positive allosteric modulator (AMPA-PAM) possessing procognitive, neurotrophic properties and enhancing synaptic plasticity. Here, we investigated the antidepressant/anxiolytic-like effects of S 47445 in a mouse model of anxiety/depression based on chronic corticosterone administration (CORT) and in the Chronic Mild Stress (CMS) model in rats. Four doses of S 47445 (0.3 to 10 mg/kg, oral route, 4 and 5 weeks, respectively) were assessed in both models. In mouse, behavioral effects were tested in various anxiety-and depression-related behaviors : the elevated plus maze (EPM), open field (OF), splash test (ST), forced swim test (FST), tail suspension test (TST), fur coat state and novelty suppressed feeding (NSF) as well as on hippocampal neurogenesis and dendritic arborization in comparison to chronic fluoxetine treatment (18 mg/kg, p.o.). In rats, behavioral effects of S 47445 were monitored using sucrose consumption and compared to those of imipramine or venlafaxine (10 mg/kg, i.p.) during the whole treatment period and after withdrawal of treatments. In a mouse model of genetic ablation of hippocampal neurogenesis (GFAP-Tk model), neurogenesis dependent/independent effects of chronic S 47445 treatment were tested, as well as BDNF hippocampal expression. S 47445 reversed CORT-induced depressive-like state by increasing grooming duration and reversing coat state’s deterioration. S 47445 also decreased the immobility duration in TST and FST. The highest doses (3 and 10 mg/kg) seem the most effective for antidepressant-like activity in CORT mice. Furthermore, S 47445 significantly reversed the anxiety phenotype observed in OF (at 1 mg/kg) and EPM (from 1 mg/kg). In the CMS rat model, S 47445 (from 1 mg/kg) demonstrated a rapid onset of effect on anhedonia compared to venlafaxine and imipramine. In the CORT model, S 47445 demonstrated significant neurogenic effects on proliferation, survival and maturation of hippocampal newborn neurons at doses inducing an antidepressant-like effect. It also corrected CORT-induced deficits of growth and arborization of dendrites. Finally, the antidepressant/anxiolytic-like activities of S 47445 required adult hippocampal neurogenesis in the novelty suppressed feeding test contrary to OF, EPM and ST. The observed increase in hippocampal BDNF levels could be one of the mechanisms of S 47445 responsible for the adult hippocampal neurogenesis increase. Altogether, S 47445 displays robust antidepressant-anxiolytic-like properties after chronic administration through neurogenesis dependent/independent mechanisms and neuroplastic activities. The AMPA-PAM S 47445 could have promising therapeutic potential for the treatment of major depressive disorders or generalized anxiety disorders.

Actions of Brain-Derived Neurotrophic Factor and Glucocorticoid Stress in Neurogenesis

“…It is very interesting whether the increased BDNF directly stimulate to produce new-born neurons or not because the activation of latent stem/progenitor cells by neuronal activity itself in the adult hippocampus has been reported [ 24 ]. Recently, an Antidepressant-Like Effect of S 47445 (8-cyclopropyl-3-[2-(3-fluorophenyl)ethyl]-7,8-dihydro-3H-[1,3]oxazino[6,5-g][1,2,3] benzotriazine-4,9-dione), a positive modulator of AMPA-type glutamate receptors, has been reported [ 25 ]. In animals received chronic corticosterone (a rodent glucocorticoid) administration and exhibited anxiety/depression-like behaviors, treatment of S 47445 reversed the depression-like behaviors and showed neurogenic effects including cell proliferation, survival promotion, and maturation of hippocampal newborn neurons.…”

“…In animals received chronic corticosterone (a rodent glucocorticoid) administration and exhibited anxiety/depression-like behaviors, treatment of S 47445 reversed the depression-like behaviors and showed neurogenic effects including cell proliferation, survival promotion, and maturation of hippocampal newborn neurons. Interestingly, when neurogenesis deficient mice in which GFAP-positive progenitor cells were killed by ganciclovir treatment [ 26 ] was examined, S 47445 increased hippocampal BDNF and improved several anxiety/depression-like behaviors [ 25 ], suggesting a neurogenesis-independent process in the recovery of anxiety/depression-like behaviors. Furthermore, it has been demonstrated that Norbin, an endogenous regulator of metabotropic glutamate receptor 5 (mGluR5), promoted hippocampal neurogenesis [ 27 ].…”

Vortioxetine Improves Context Discrimination in Mice Through a Neurogenesis Independent Mechanism

“…Of note, it is important to highlight that administration of GCV for 4 weeks to ablate neurogenesis may have induced compensatory effects or lead to different coping strategies during the CD test. GCV was administered during CD protocol until the end of the experiment as described in ( Mendez-David et al, 2017 ), thus preventing the resume of AHN ( Sakalem et al, 2017 ). As mentioned above several studies support a role of adult neurogenesis in rodent models of PS, however other studies do not find a clear link ( Becker, 2016 ).…”

“…In order to assess the role of AHN on CD, glial fibrillary acidic protein (GFAP)-Thymidine kinase (TK + ) male mice were used. Mice were generated as previously described ( Mendez-David et al, 2017 ). An agreement (license L-O 15-2015/0) between the NIH and the Université Paris-Sud provides CESP/UMRS 1178 laboratory with the use of transgenic mice that express herpes simplex virus (HSV) TK under control of the GFAP promoter (GFAP-TK mice), as previously described ( Snyder et al, 2011 ; Mendez-David et al, 2017 ) and developed in the laboratory of Dr. Heather Cameron of the National Institute of Mental Health (NIMH).…”

“…GCV treatment continued until the end of the study. GCV was weekly removed on Friday, Saturday, and Sunday as described in Lugert et al (2017) and Mendez-David et al (2017) . GFAP-TK-positive (GFAP-TK + ) mice received regular chow (NON-GCV) or VGCV, the L -valyl ester of ganciclovir, has a high (approximately 85%) bioavailability and is rapidly converted into ganciclovir by intestinal and hepatic esterases after oral administration.…”