S 47445 counteracts the behavioral manifestations and hippocampal neuroplasticity changes in bulbectomized mice.

S 47445 is a positive allosteric modulator of glutamate AMPA-type receptors that possesses procognitive, neurotrophic and enhancing synaptic plasticity properties. Its chronic administration promotes antidepressant- and anxiolytic-like effects in different rodent models of depression. We have evaluated the behavioral effects of S 47445 in the bilateral olfactory bulbectomy mice model (OB) and the adaptive changes in those proteins associated to brain neuroplasticity (BDNF and mTOR pathway).

Drug-receptor kinetics and sigma-1 receptor affinity differentiate clinically evaluated histamine H receptor antagonists.

The histamine H receptor is a G protein-coupled receptor (GPCR) drug target that is highly expressed in the CNS, where it acts as both an auto- and hetero-receptor to regulate neurotransmission. As such, it has been considered as a relevant target in disorders as varied as Alzheimer's disease, schizophrenia, neuropathic pain and attention deficit hyperactivity disorder. A range of competitive antagonists/inverse agonists have progressed into clinical development, with pitolisant approved for the treatment of narcolepsy.

α- and β-Adrenoreceptor-Mediated Efficacy of the Atypical Antidepressant Agomelatine Combined With Gabapentin to Suppress Allodynia in Neuropathic Rats With Ligated Infraorbital or Sciatic Nerve.

Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves has specific characteristics and responds differently to alleviating drugs at cephalic versus extracephalic level. This is especially true for tricyclic antidepressants currently used for alleviating neuropathic pain in humans which are less effective against cephalic neuropathic pain. Whether this also applies to the antidepressant agomelatine, with its unique pharmacological properties as MT/MT melatonin receptor agonist and 5-HT/5-HT serotonin receptor antagonist, has been investigated in two rat models of neuropathic pain.

The reduction in glutamate release is predictive of cognitive and emotional alterations that are corrected by the positive modulator of AMPA receptors S 47445 in perinatal stressed rats.

S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties. Here, the drug was assessed in the perinatal stress (PRS) rat model, known to have a high predictive validity with monoaminergic antidepressants. The effects of a chronic treatment (i.

Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice.

Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance.

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

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.

Increased Aβ-α7-like nicotinic acetylcholine receptor complex level in lymphocytes is associated with apolipoprotein E4-driven Alzheimer's disease pathogenesis.

Background: The apolipoprotein E ε4 (APOE4) genotype is a prominent late-onset Alzheimer's disease (AD) risk factor. ApoE4 disrupts memory function in rodents and may contribute to both plaque and tangle formation.

Methods: Coimmunoprecipitation and Western blot detection were used to determine: 1) the effects of select fragments from the apoE low-density lipoprotein (LDL) binding domain and recombinant apoE subtypes on amyloid beta (Aβ)-α7 nicotinic acetylcholine receptor (α7nAChR) interaction and tau phosphorylation in rodent brain synaptosomes; and 2) the level of Aβ-α7nAChR complexes in matched controls and patients with mild cognitive impairment (MCI) and dementia due to AD with known APOE genotypes.

Upregulation of neurotrophins by S 47445, a novel positive allosteric modulator of AMPA receptors in aged rats.

At molecular levels, it has been shown that aging is associated with alterations in neuroplastic mechanisms. In this study, it was examined if the altered expression of neurotrophins observed in aged rats could be corrected by a chronic treatment with S 47445 (1-3-10mg/kg, p.o.

Effect of agomelatine on memory deficits and hippocampal gene expression induced by chronic social defeat stress in mice.

Chronic stress is known to induce not only anxiety and depressive-like phenotypes in mice but also cognitive impairments, for which the action of classical antidepressant compounds remains unsatisfactory. In this context, we investigated the effects of chronic social defeat stress (CSDS) on anxiety-, social- and cognitive-related behaviors, as well as hippocampal Bdnf, synaptic plasticity markers (PSD-95, Synaptophysin, Spinophilin, Synapsin I and MAP-2), and epigenetic modifying enzymes (MYST2, HDAC2, HDAC6, MLL3, KDM5B, DNMT3B, GADD45B) gene expression in C57BL/6J mice. CSDS for 10 days provoked long-lasting anxious-like phenotype in the open field and episodic memory deficits in the novel object recognition test.

S 38093, a histamine H antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice.

Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN.

The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice.

Donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer's disease patients. An alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both histaminergic and cholinergic pathways, to create a synergistic effect. To that aim, 14 month old C57/Bl6 mice were administered per oesophagy during nine consecutive days with Donepezil (at 0.

Agomelatine: a new opportunity to reduce neuropathic pain-preclinical evidence.

Antidepressants are first-line treatments of neuropathic pain but not all these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as an MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect norepinephrine release. Melatonin, serotonin, and norepinephrine have been involved in the pathophysiology of neuropathic pain.

Isoform-Specific Biased Agonism of Histamine H3 Receptor Agonists.

The human histamine H receptor (hHR) is subject to extensive gene splicing that gives rise to a large number of functional and nonfunctional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signaling, this has not been studied for the HR; further, it is unknown whether splice variants of the same receptor engender the same or differential biased signaling. Herein, we profiled the pharmacology of histamine receptor agonists at the two most abundant hHR splice variants (hHR and hHR) across seven signaling endpoints.

Agomelatine affects rat suprachiasmatic nucleus neurons via melatonin and serotonin receptors.

Aims: The hypothalamic suprachiasmatic nucleus (SCN), which functions as a circadian pacemaker in mammals, is influenced by melatonin and serotonin. Agomelatine, which acts as an antidepressant and can synchronize disturbed circadian rhythms, displays a unique mechanism of action involving both melatonergic agonist and 5-HT2C antagonist properties. This study investigated the dose-dependent effects of agomelatine, melatonin and a selective 5-HT2C receptor antagonist, S32006, on SCN neurons in an in vitro slice preparation.

Behavioral and neurochemical characterization of TrkB-dependent mechanisms of agomelatine in glucocorticoid receptor-impaired mice.

Growing evidence indicates that impairment of the stress response, in particular the negative feedback regulation mechanism exerted by the hypothalamo-pituitary-adrenal (HPA) axis, might be responsible for the hippocampal atrophy observed in depressed patients. Antidepressants, possibly through the activation of BDNF signaling, may enhance neuroplasticity and restore normal hippocampal functions. In this context, glucocorticoid receptor-impaired (GR-i) mice-a transgenic mouse model of reduced GR-induced negative feedback regulation of the HPA axis-were used to investigate the role of BDNF/TrkB signaling in the behavioral and neurochemical effects of the new generation antidepressant drug, agomelatine.

Hippocampal and behavioral dysfunctions in a mouse model of environmental stress: normalization by agomelatine.

Stress-induced alterations in neuronal plasticity and in hippocampal functions have been suggested to be involved in the development of mood disorders. In this context, we investigated in the hippocampus the activation of intracellular signaling cascades, the expression of epigenetic markers and plasticity-related genes in a mouse model of stress-induced hyperactivity and of mixed affective disorders. We also determined whether the antidepressant drug agomelatine, a MT1/MT2 melatonergic receptor agonist/5-HT2C receptor antagonist, could prevent some neurobiological and behavioral alterations produced by stress.

Repeated restraint stress-induced atrophy of glutamatergic pyramidal neurons and decreases in glutamatergic efflux in the rat amygdala are prevented by the antidepressant agomelatine.

Major depressive illness is among the most prevalent neuropsychiatric disorders and is associated with neuroplasticity deficits in limbic structures such as the amygdala. Since exposure to stressful life events is proposed to contribute to depressive illness, our recent studies examined the effects of stress on amygdalar neuroplasticity. These studies determined that repeated stress elicits deficits in glutamatergic activity in the amygdala, neuroplasticity deficits that can be prevented by some but not all antidepressants.

Evaluation of the effects of therapeutic and supratherapeutic doses of agomelatine on the QT/QTc interval: a phase I, randomized, double-blind, placebo-controlled and positive-controlled, crossover thorough QT/QTc study conducted in healthy volunteers.

: The effects of the antidepressant agomelatine up to a supratherapeutic dose (400 mg, single dose) on the QT corrected (QTc) interval were assessed in a randomized, double-blind, placebo- and positive-controlled, crossover thorough QT/QTc study in young healthy volunteers (29 males and 31 females). The primary criterion was the study of male or female population-derived QT-corrected interval (QTcP). The main analysis on the QTcP demonstrated that among the 10 postdose measurement times planned, the largest 1-sided 95% confidence interval upper bound of the difference between agomelatine 50 mg and placebo-adjusted means, and 1 of the differences between agomelatine 400 mg and placebo-adjusted means were both strictly inferior to the 10 millisecond upper-bound threshold of regulatory concern.

Agomelatine: mechanism of action and pharmacological profile in relation to antidepressant properties.

Agomelatine behaves both as a potent agonist at melatonin MT1 and MT2 receptors and as a neutral antagonist at 5-HT2C receptors. Accumulating evidence in a broad range of experimental procedures supports the notion that the psychotropic effects of agomelatine are due to the synergy between its melatonergic and 5-hydroxytryptaminergic effects. The recent demonstration of the existence of heteromeric complexes of MT1 and MT2 with 5-HT2C receptors at the cellular level may explain how these two properties of agomelatine translate into a synergistic action that, for example, leads to increases in hippocampal proliferation, maturation and survival through modulation of multiple cellular pathways (increase in trophic factors, synaptic remodelling, glutamate signalling) and key targets (early genes, kinases).

The effects of antidepressant treatment in prenatally stressed rats support the glutamatergic hypothesis of stress-related disorders.

Abnormalities of synaptic transmission in the hippocampus represent an integral part of the altered programming triggered by early life stress, which enhances the vulnerability to stress-related disorders in the adult life. Rats exposed to prenatal restraint stress (PRS) develop enduring biochemical and behavioral changes characteristic of an anxious/depressive-like phenotype. Most neurochemical abnormalities in PRS rats are found in the ventral hippocampus, a region that encodes memories related to stress and emotions.

Like melatonin, agomelatine (S20098) increases the amplitude of oscillations of two clock outputs: melatonin and temperature rhythms.

Depression and biological rhythms disturbances are strongly associated. Agomelatine is an antidepressant with melatoninergic MT1-MT2 agonist and serotoninergic 5-HT2c antagonist properties. Both melatonin and 5-HT are known to modulate circadian rhythmicity controlled by the endogenous clock located in the suprachiasmatic nuclei (SCN).

Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes.

Background: Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders. Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex. Agomelatine, a new antidepressant endowed with MT1/MT2 agonist and 5-HT2C serotonergic antagonist properties, has shown efficacy at both preclinical and clinical levels.

Pharmacological or genetic blockade of the dopamine D3 receptor increases cell proliferation in the hippocampus of adult mice.

Dopamine plays an important role in cellular processes controlling the functional and structural plasticity of neurons, as well as their generation and proliferation, both in the developing and the adult brain. The precise roles of individual dopamine receptors subtypes in adult neurogenesis remain poorly defined, although D3 receptors are known to be involved in neurogenesis in the subventricular zone. By contrast, very few studies have addressed the influence of dopamine and D3 receptors upon neurogenesis in the subgranular zone of the hippocampus, an issue addressed herein employing constitutive D3 receptor knockout mice, or chronic exposure to the preferential D3 receptor antagonist, S33138.

The antidepressant agomelatine inhibits stress-mediated changes in amino acid efflux in the rat hippocampus and amygdala.

Agomelatine is a potent melatonergic (MT1 and MT2) receptor agonist and 5HT(2C) antagonist that is an effective antidepressant in animal models of depression and in patients suffering from depression. Our recent studies revealed that acute restraint stress increases extracellular levels of glutamate and GABA and that these increases in amino acid efflux are inhibited by some but not all antidepressants. In view of the increasing evidence supporting a role of amino acids in the pathology of depression, the current study examined whether acute stress-mediated changes in glutamate and GABA neurotransmission are modulated by agomelatine.