RESUMO
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. We have recently demonstrated a causal link between the reduction of glutamate release in the ventral hippocampus and anxiety-like behavior in PRS rats. To confer pharmacological validity to the glutamatergic hypothesis of stress-related disorders, we examined whether chronic treatment with two antidepressants with different mechanisms of action could correct the defect in glutamate release and associated behavioral abnormalities in PRS rats. Adult unstressed or PRS rats were treated daily with either agomelatine (40 mg/kg, i.p.) or fluoxetine (5 mg/kg, i.p.) for 21 d. Both treatments reversed the reduction in depolarization-evoked glutamate release and in the expression of synaptic vesicle-associated proteins in the ventral hippocampus of PRS rats. Antidepressant treatment also corrected abnormalities in anxiety-/depression-like behavior and social memory performance in PRS rats. The effect on glutamate release was strongly correlated with the improvement of anxiety-like behavior and social memory. These data offer the pharmacological demonstration that glutamatergic hypofunction in the ventral hippocampus lies at the core of the pathological phenotype caused by early life stress and represents an attractive pharmacological target for novel therapeutic strategies.
Assuntos
Antidepressivos/uso terapêutico , Ácido Glutâmico/metabolismo , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Ansiedade/psicologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/psicologia , Feminino , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/psicologia , Resultado do TratamentoRESUMO
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. RESULTS: Chronic treatment with agomelatine, or with the reference drug venlafaxine, induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion. No changes were observed in GABA release. This effect was accompanied by reduced accumulation of SNARE protein complexes, the key molecular effector of vesicle docking, priming and fusion at presynaptic membranes. CONCLUSIONS: Our data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus. Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release.
Assuntos
Acetamidas/farmacologia , Antidepressivos/farmacologia , Cicloexanóis/farmacologia , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Sinaptossomos/efeitos dos fármacos , Análise de Variância , Animais , Ionóforos de Cálcio/farmacologia , Ionomicina/farmacologia , Masculino , Cloreto de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas SNARE/metabolismo , Sintaxina 1/metabolismo , Cloridrato de Venlafaxina , Ácido gama-Aminobutírico/metabolismoRESUMO
Agomelatine is a novel antidepressant acting as an MT1/MT2 melatonin receptor agonist/5-HT2C serotonin receptor antagonist. Because of its peculiar pharmacological profile, this drug caters the potential to correct the abnormalities of circadian rhythms associated with mood disorders, including abnormalities of the sleep/wake cycle. Here, we examined the effect of chronic agomelatine treatment on sleep architecture and circadian rhythms of motor activity using the rat model of prenatal restraint stress (PRS) as a putative 'aetiological' model of depression. PRS was delivered to the mothers during the last 10 d of pregnancy. The adult progeny ('PRS rats') showed a reduced duration of slow wave sleep, an increased duration of rapid eye movement (REM) sleep, an increased number of REM sleep events and an increase in motor activity before the beginning of the dark phase of the light/dark cycle. In addition, adult PRS rats showed an increased expression of the transcript of the primary response gene, c-Fos, in the hippocampus just prior to the beginning of the dark phase. All these changes were reversed by a chronic oral treatment with agomelatine (2000 ppm in the diet). The effect of agomelatine on sleep was largely attenuated by treatment with the MT1/MT2 melatonin receptor antagonist, S22153, which caused PRS-like sleep disturbances on its own. These data provide the first evidence that agomelatine corrects sleep architecture and restores circadian homeostasis in a preclinical model of depression and supports the value of agomelatine as a novel antidepressant that resynchronizes circadian rhythms under pathological conditions.
Assuntos
Acetamidas/uso terapêutico , Transtornos Cronobiológicos/tratamento farmacológico , Hipnóticos e Sedativos/uso terapêutico , Transtornos dos Movimentos/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Transtornos do Sono-Vigília/tratamento farmacológico , Análise de Variância , Animais , Animais Recém-Nascidos , Nível de Alerta/efeitos dos fármacos , Autorradiografia , Transtornos Cronobiológicos/etiologia , Modelos Animais de Doenças , Esquema de Medicação , Eletroencefalografia , Eletromiografia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Transtornos dos Movimentos/etiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/patologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Melatonina/antagonistas & inibidores , Restrição Física/efeitos adversos , Transtornos do Sono-Vigília/etiologia , Tiofenos/farmacologiaRESUMO
Morphological alterations of the endosomal compartment have been widely described in post-mortem brains from Alzheimer's disease (AD) patients and subjects with Down syndrome (DS) who are at high risk for AD. Immunostaining with antibodies against endosomal markers such as Early Endosome Antigen 1 (EEA1) revealed increased size of EEA1-positive puncta. In DS, peripheral cells such as peripheral blood mononuclear cells (PBMCs) and fibroblasts, share similar phenotype even in the absence of AD. We previously found that PBMCs from AD patients have larger EEA1-positive puncta, correlating with brain amyloid load. Here we analysed the endosomal compartment of fibroblasts from a very well characterised cohort of AD patients (IMABio3) who underwent thorough clinical, imaging and biomarkers assessments. Twenty-one subjects were included (7 AD with mild cognitive impairment (AD-MCI), 7 AD with dementia (AD-D) and 7 controls) who had amyloid-PET at baseline (PiB) and neuropsychological tests at baseline and close to skin biopsy. Fibroblasts isolated from skin biopsies were immunostained with anti-EEA1 antibody and imaged using a spinning disk microscope. Endosomal compartment ultrastructure was also analysed by electron microscopy. All fibroblast lines were genotyped and their AD risk factors identified. Our results show a trend to an increased EEA1-positive puncta volume in fibroblasts from AD-D as compared to controls (p.adj = 0.12) and reveal enhanced endosome area in fibroblasts from AD-MCI and AD-AD versus controls. Larger puncta size correlated with PiB retention in different brain areas and with worse cognitive scores at the time of biopsy as well as faster decline from baseline to the time of biopsy. Finally, we identified three genetic risk factors for AD (ABCA1, COX7C and MYO15A) that were associated with larger EEA1 puncta volume. In conclusion, the endosomal compartment in fibroblasts could be used as cellular peripheral biomarker for both amyloid deposition and cognitive decline in AD patients.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Amiloide , Peptídeos beta-Amiloides , Endossomos/patologia , Fibroblastos , Leucócitos Mononucleares , Tomografia por Emissão de PósitronsRESUMO
Agomelatine (S20098) is a novel antidepressant drug with melatonergic agonist and 5-HT2C receptor antagonist properties, displaying antidepressant/anxiolytic-like properties in animal models and in humans. In a depression/anxiety-like mouse model in which the response of the HPA axis is blunted, we investigated whether agomelatine could reverse behavioural deficits related to depression/anxiety compared to the classical selective serotonin reuptake inhibitor, fluoxetine. Adult mice were treated for 8 wk with either vehicle or corticosterone (35 µg/ml.d) via drinking water. During the final 4 wk, animals were treated with vehicle, agomelatine (10 or 40 mg/kg i.p.) or fluoxetine (18 mg/kg i.p.) and tested in several behavioural paradigms and also evaluated for home-cage activity. Our results showed that the depressive/anxiety-like phenotype induced by corticosterone treatment is reversed by either chronic agomelatine or fluoxetine treatment. Moreover, agomelatine increased the dark/light ratio of home-cage activity in vehicle-treated mice and reversed the alterations in this ratio induced by chronic corticosterone, suggesting a normalization of disturbed circadian rhythms. Finally, we investigated the effects of this new antidepressant on neurogenesis. Agomelatine reversed the decreased cell proliferation in the whole hippocampus in corticosterone-treated mice and increased maturation of newborn neurons in both vehicle- and corticosterone-treated mice. Overall, the present study suggests that agomelatine, with its distinct mechanism of action based on the synergy between the melatonergic agonist and 5-HT2C antagonist properties, provides a distinct antidepressant/anxiolytic spectrum including circadian rhythm normalization.
Assuntos
Acetamidas/farmacologia , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Animais , Transtornos de Ansiedade/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Corticosterona , Dendritos/efeitos dos fármacos , Dendritos/fisiologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologiaRESUMO
The antidepressant agomelatine acts as a melatonergic receptor (MT(1)/MT(2)) agonist and 5-HT(2C) receptor antagonist. Agomelatine has demonstrated efficacy in treating depression, but its neurobiological effects merit further investigation. Preclinical studies reported that agomelatine enhances adult hippocampal neurogenesis and increases expression of several neuroplasticity-associated molecules. Recently, we showed that agomelatine normalizes hippocampal neuronal activity and promotes neurogenesis in the stress-compromised brain. To characterize further the effects of this antidepressant in the stressed brain, here we investigated whether it induces changes in the expression of synapsin I (SynI), a regulator of synaptic transmission and plasticity. Adult male rats were subjected to daily footshock stress and agomelatine treatment for 3 weeks. Their brains were subsequently stained for total and phosphorylated SynI. Chronic footshock and agomelatine induced region-specific changes in SynI expression. Whereas chronic stress increased total SynI expression in all layers of the medial prefrontal cortex, agomelatine treatment abolished some of these effects. Furthermore, chronic agomelatine administration decreased total SynI expression in the hippocampal subregions of both stressed and nonstressed rats. Importantly, chronic stress decreased the fraction of phosphorylated SynI in all layers of the medial prefrontal cortex as well as selectively in the outer and middle molecular layers of the hippocampal dentate gyrus. These stress effects were at least partially abolished by agomelatine. Altogether, our data show that chronic stress and agomelatine treatment induce region-specific changes in SynI expression and its phosphorylation. Moreover, agomelatine partially counteracts the stress effects on SynI, suggesting a modulation of synaptic function by this antidepressant.
Assuntos
Acetamidas/farmacologia , Antidepressivos/farmacologia , Química Encefálica/efeitos dos fármacos , Química Encefálica/genética , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Estresse Psicológico/tratamento farmacológico , Sinapsinas/genética , Animais , Doença Crônica , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Estresse Psicológico/metabolismo , Sinapsinas/biossíntese , Sinapsinas/metabolismoRESUMO
Major depression is associated with reduced hippocampal volume linked to stress and high glucocorticoid secretion. Glucocorticoid receptor-impaired (GR-i) mice, a transgenic model for affective disorders with hypothalamic-pituitary-adrenal (HPA) axis feedback control deficit, were used to assess the antidepressant-like effects of the mixed melatonin receptor agonist/5-HT(2C) receptor antagonist, agomelatine, compared to the selective 5-HT reuptake inhibitor (SSRI), fluoxetine, on hippocampal neurogenesis, GR and BDNF expression and antidepressant-responsive behaviour (tail suspension test, TST). GR-i and paired wild-type (WT) mice were given acute or chronic (21 d) treatment with these drugs. Both hippocampal cell proliferation and BDNF mRNA expression were down-regulated in GR-i mice, and these alterations were reversed by chronic agomelatine and fluoxetine treatments, whereas GR mRNA down-regulation was reversed only by agomelatine. Furthermore, chronic agomelatine, but not fluoxetine, increased survival of newly formed cells in the ventral part of the hippocampus without changing their phenotypic differentiation into neurons. In the TST, the enhanced immobility of GR-i mice was reduced to WT level by acute (but not chronic) fluoxetine and chronic (but not acute) agomelatine. These results indicate that agomelatine reversed the neuroplastic changes and helpless behaviour associated with HPA axis alterations in GR-i mice, suggesting neurobiological and behavioural effects mostly similar to those typically seen with classical antidepressants such as fluoxetine, but through clearly distinct mechanisms.
Assuntos
Acetamidas/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Receptores de Glucocorticoides/deficiência , Animais , Comportamento Animal/fisiologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Bromodesoxiuridina/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Proliferação de Células/efeitos dos fármacos , Proteínas do Domínio Duplacortina , Esquema de Medicação , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Elevação dos Membros Posteriores/métodos , Hipocampo/citologia , Hipocampo/metabolismo , Marcação In Situ das Extremidades Cortadas/métodos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropeptídeos/metabolismo , RNA Mensageiro/metabolismo , Ratos , Receptores de Glucocorticoides/metabolismoRESUMO
Agomelatine, a novel antidepressant with established clinical efficacy, acts as a melatonin receptor agonist and 5-HT(2C) receptor antagonist. As stress is a significant risk factor in the development of depression, we sought to determine if chronic agomelatine treatment would block the stress-induced impairment of memory in rats trained in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. Moreover, since neural cell adhesion molecule (NCAM) is known to be critically involved in memory consolidation and synaptic plasticity, we evaluated the effects of agomelatine on NCAM, and polysialylated NCAM (PSA-NCAM) expression in rats given spatial memory training with or without predator stress. Adult male rats were pre-treated with agomelatine (10 mg/kg i.p., daily for 22 d), followed by a single day of RAWM training and memory testing. Rats were given 12 training trials and then they were placed either in their home cages (no stress) or near a cat (predator stress). Thirty minutes later the rats were given a memory test trial followed immediately by brain extraction. We found that: (1) agomelatine blocked the predator stress-induced impairment of spatial memory; (2) agomelatine-treated stressed, as well as non-stressed, rats exhibited a rapid training-induced increase in the expression of synaptic NCAM in the ventral hippocampus; and (3) agomelatine treatment blocked the water-maze training-induced decrease in PSA-NCAM levels in both stressed and non-stressed animals. This work provides novel observations which indicate that agomelatine blocks the adverse effects of stress on hippocampus-dependent memory and activates molecular mechanisms of memory storage in response to a learning experience.
Assuntos
Acetamidas/farmacologia , Antidepressivos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Ácidos Siálicos/metabolismo , Percepção Espacial/efeitos dos fármacos , Acetamidas/uso terapêutico , Análise de Variância , Animais , Antidepressivos/uso terapêutico , Corticosterona/sangue , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática/métodos , Deficiências da Aprendizagem/tratamento farmacológico , Deficiências da Aprendizagem/etiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologiaRESUMO
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 MT1/MT2 melatonin receptor agonist and 5-HT2B/5-HT2C serotonin receptor antagonist, has been investigated in two rat models of neuropathic pain. Acute treatments were performed 2 weeks after unilateral chronic constriction (ligation) injury to the sciatic nerve (CCI-SN) or the infraorbital nerve (CCI-ION), when maximal mechanical allodynia had developed in ipsilateral hindpaw or vibrissal pad, respectively, in Sprague-Dawley male rats. Although agomelatine (45 mg/kg i.p.) alone was inactive, co-treatment with gabapentin, at an essentially ineffective dose (50 mg/kg i.p.) on its own, produced marked anti-allodynic effects, especially in CCI-ION rats. In both CCI-SN and CCI-ION models, suppression of mechanical allodynia by 'agomelatine + gabapentin' could be partially mimicked by the combination of 5-HT2C antagonist (SB 242084) + gabapentin, but not by melatonin or 5-HT2B antagonist (RS 127445, LY 266097), alone or combined with gabapentin. In contrast, pretreatment by idazoxan, propranolol or the ß2 antagonist ICI 118551 markedly inhibited the anti-allodynic effect of 'agomelatine + gabapentin' in both CCI-SN and CCI-ION rats, whereas pretreatment by the MT1/MT2 receptor antagonist S22153 was inactive. Altogether these data indicate that 'agomelatine + gabapentin' is a potent anti-allodynic combination at both cephalic and extra-cephalic levels, whose action implicates α2- and ß2-adrenoreceptor-mediated noradrenergic neurotransmission.
RESUMO
OBJECTIVE: In this study we investigated the distribution of melatonergic receptors in the tree shrew brain. The psychosocial stress in the tree shrew is a validated model of depression with disturbance of circadian rhythms. METHODS: Given the role of melatonin in the modulation of circadian rhythms, we determined by autoradiography the distribution of binding sites of 2-[125I]-MLT, a ligand for the two melatonergic receptors MT1 and MT2, in the tree shrew brain focusing mostly on the suprachiasmatic nucleus (SCN), the biological clock involved in resynchronization of circadian rhythms. We also analyzed the distribution of 2-[125I]-MLT in other brain areas involved in regulation of mood. RESULTS: Specific binding of 2-[125I]-MLT was found in the SCN. In addition, several structures in the tree shrew brain were labeled, among them the pars tuberalis, the cerebellum, structures of the hippocampal formation and dopaminergic areas such as the caudate putamen and nucleus accumbens, providing other potential targets of psychosocial stress in the tree shrew, in addition to the SCN. CONCLUSIONS: The demonstration of melatonergic receptors in these brain areas supports their probable involvement in the behavioural, neuroendocrine and circadian rhythms disturbances observed in the psychosocial stress model of depression in the tree shrew.
Assuntos
Receptores de Melatonina/análise , Núcleo Supraquiasmático/química , Acetamidas/farmacologia , Animais , Autorradiografia , Sítios de Ligação , Encéfalo/metabolismo , Ritmo Circadiano , Feminino , Melatonina/metabolismo , Memória , Receptores de Melatonina/fisiologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , TupaiidaeRESUMO
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. Yet, no study has been conducted to determine agomelatine effects on neuropathic pain in animal models. Using 3 rat models of neuropathic pain of toxic (oxaliplatin/OXA), metabolic (streptozocin/STZ), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, we investigated the antihypersensitivity effect of acute and repeated agomelatine administration. We then determined the influence of melatonergic, 5-HT2C, α-2 and ß-1/2 adrenergic receptor antagonists in the antihypersensitivity effect of agomelatine. The effect of the combination of agomelatine + gabapentin was evaluated using an isobolographic approach. In STZ and CCI models, single doses of agomelatine significantly and dose dependently reduced mechanical hypersensitivity. After daily administrations for 2 weeks, this effect was confirmed in the CCI model and agomelatine also displayed a marked antihypersensitivity effect in the OXA model. The antihypersensitivity effect of agomelatine involved melatonergic, 5-HT2C, and α-2 adrenergic receptors but not beta adrenoceptors. The isobolographic analysis demonstrated that the combination of agomelatine + gabapentin had additive effects. Agomelatine exerts a clear-cut antihypersensitivity effect in 3 different neuropathic pain models. Its effect is mediated by melatonergic and 5-HT2C receptors and, although agomelatine has no affinity, also by α-2 adrenergic receptors. Finally, agomelatine combined with gabapentin produces an additive antihypersensitivity effect.
Assuntos
Acetamidas/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Neuralgia/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Aminas/uso terapêutico , Animais , Antineoplásicos/toxicidade , Constrição Patológica/complicações , Ácidos Cicloexanocarboxílicos/uso terapêutico , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Gabapentina , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Idazoxano/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Neuralgia/etiologia , Compostos Organoplatínicos/toxicidade , Oxaliplatina , Medição da Dor , Ratos , Ratos Sprague-Dawley , Tiofenos/uso terapêutico , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
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. While total Bdnf mRNA level was unchanged, Bdnf exon IV, MAP-2, HDAC2, HDAC6 and MLL3 gene expression was significantly decreased in the CSDS mouse hippocampus. In CSDS mice treated 3 weeks with 50 mg/kg/d agomelatine, an antidepressant with melatonergic receptor agonist and 5-HT2C receptor antagonist properties, the anxious-like phenotype was not reversed, but the treatment successfully prevented the cognitive impairments and hippocampal gene expression modifications. Altogether, these data evidenced that, in mice, agomelatine was effective in alleviating stress-induced altered cognitive functions, possibly through a mechanism involving BDNF signaling, synaptic plasticity and epigenetic remodeling.
Assuntos
Acetamidas/administração & dosagem , Disfunção Cognitiva/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/genética , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Transtorno Depressivo/patologia , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Transtornos da Memória/genética , Transtornos da Memória/patologia , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Estresse Psicológico/genética , Estresse Psicológico/patologia , Sinapsinas/genética , Sinaptofisina/genéticaRESUMO
Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid-beta (Abeta) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of Abeta. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-beta precursor protein (KPI-APP) followed by a shift from alpha-secretase to beta-secretase-mediated APP processing. This shift is a result of the inhibition of the alpha-secretase candidate tumor necrosis factor-alpha converting enzyme (TACE) when associated with neuronal KPI-APPs. This KPI-APP/TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal Abeta secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase Abeta production and represent a causal risk factor for developing AD.
Assuntos
Peptídeos beta-Amiloides/biossíntese , Endopeptidases/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/genética , Animais , Ácido Aspártico Endopeptidases , Células Cultivadas , Endopeptidases/genética , Agonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Camundongos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Receptores de N-Metil-D-Aspartato/fisiologiaRESUMO
A major domain of depression is decreased motivation for reward. Translational automated tests can be applied in humans and animals to study operant reward behaviour, aetio-pathophysiology underlying deficits therein, and effects of antidepressant treatment. Three inter-related experiments were conducted to investigate depression-relevant effects of chronic psychosocial stress on operant behaviour in mice. (A) Non-manipulated mice were trained on a complex reversal learning (CRL) test with sucrose reinforcement; relative to vehicle (VEH), acute antidepressant agomelatine (AGO, 25mg/kg p.o.) increased reversals. (B) Mice underwent chronic social defeat (CSD) or control handling (CON) on days 1-15, and were administered AGO or VEH on days 10-22. In a progressive ratio schedule motivation test for sucrose on day 15, CSD mice made fewer responses; AGO tended to reverse this effect. In a CRL test on day 22, CSD mice completed fewer reversals; AGO tended to increase reversals in CSD mice associated with an adaptive increase in perseveration. (C) Mice with continuous operant access to water and saccharin solution in the home cage were exposed to CSD or CON; CSD mice made fewer responses for saccharin and water and drank less saccharin in the active period, and drank more water in the inactive period. In a separate CSD cohort, repeated AGO was without effect on these home cage operant and consummatory changes. Overall, this study demonstrates that psychosocial stress in mice leads to depression-relevant decreases in motivation and cognition in operant reward tests; partial reversal of these deficits by AGO provides evidence for predictive validity.
Assuntos
Acetamidas/farmacologia , Antidepressivos/farmacologia , Condicionamento Operante/efeitos dos fármacos , Motivação/efeitos dos fármacos , Recompensa , Estresse Psicológico/tratamento farmacológico , Acetamidas/farmacocinética , Animais , Antidepressivos/farmacocinética , Automação Laboratorial , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Sacarose Alimentar , Dominação-Subordinação , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Indóis/farmacologia , Masculino , Melatonina/farmacologia , Camundongos Endogâmicos C57BL , Modelos Animais , Piridinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Reversão de Aprendizagem/efeitos dos fármacos , Sacarina , Antagonistas da Serotonina/farmacologiaRESUMO
Although transforming growth factor (TGF)-alpha, a member of the epidermal growth factor (EGF) family, has been shown to protect neurons against excitotoxic and ischemic brain injuries, its mechanism of action remains unknown. In the present study, we used in vitro models of apoptotic or necrotic paradigms demonstrating that TGF-alpha rescues neurons from N-methyl-D-aspartate (NMDA)-induced excitotoxic death, with the obligatory presence of astrocytes. Because neuronal tissue-type plasminogen activator (t-PA) release was shown to potentiate NMDA-induced excitotoxicity, we observed that TGF-alpha treatment reduced NMDA-induced increase of t-PA activity in mixed cultures of neurons and astrocytes. In addition, we showed that although TGF-alpha induces activation of the extracellular signal-regulated kinases (ERKs) in astrocytes, it failed to activate p42/p44 in neurons. Finally, we showed that TGF-alpha, by an ERK-dependent mechanism, stimulates the astrocytic expression of PAI-1, a t-PA inhibitor, which mediates the neuroprotective activity of TGF-alpha against NMDA-mediated excitotoxic neuronal death. Taken together, we indicate that TGF-alpha rescues neurons from NMDA-induced excitotoxicity in mixed cultures through inhibition of t-PA activity, involving PAI-1 overexpression by an ERK-dependent pathway in astrocytes.
Assuntos
Astrócitos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/genética , Fator de Crescimento Transformador alfa/farmacologia , Animais , Apoptose/efeitos dos fármacos , Astrócitos/citologia , Astrócitos/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , N-Metilaspartato/farmacologia , Neurônios/citologia , Fosforilação/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tecidual/metabolismoRESUMO
Abnormal deposition of Abeta (amyloid-beta peptide) is one of the hallmarks of AD (Alzheimer's disease). This peptide results from the processing and cleavage of its precursor protein, APP (amyloid-beta precursor protein). We have demonstrated previously that TGF-beta (transforming growth factor-beta), which is overexpressed in AD patients, is capable of enhancing the synthesis of APP by astrocytes by a transcriptional mechanism leading to the accumulation of Abeta. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGF-beta-dependent transcriptional activity. We report the following findings: first, TGF-beta is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the +54/+74 region of the APP promoter, named APP(TRE) (APP TGF-beta-responsive element); secondly, although this effect is mediated by a transduction pathway involving Smad3 (signalling mother against decapentaplegic peptide 3) and Smad4, Smad2 or other Smads failed to induce the activity of APP(TRE). We also observed that the APP(TRE) sequence not only responds to the Smad3 transcription factor, but also the Sp1 (signal protein 1) transcription factor co-operates with Smads to potentiate the TGF-beta-dependent activation of APP. TGF-beta signalling induces the formation of nuclear complexes composed of Sp1, Smad3 and Smad4. Overall, the present study gives new insights for a better understanding of the fine molecular mechanisms occurring at the transcriptional level and regulating TGF-beta-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-beta in the regulation of Abeta production.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Proteínas de Ligação a DNA/metabolismo , Fator de Transcrição Sp1/metabolismo , Transativadores/metabolismo , Transcrição Gênica/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Sequência de Bases , Linhagem Celular , Vison , Complexos Multiproteicos/metabolismo , Mutação/genética , Ligação Proteica/efeitos dos fármacos , Elementos de Resposta/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad , Proteína Smad3 , Proteína Smad4 , Fator de Transcrição Sp3 , Fatores de Transcrição/metabolismoRESUMO
The present double-blind, placebo-controlled study evaluates the effects of agomelatine and the selective serotonin reuptake inhibitor escitalopram on sexual dysfunction in healthy men and women. METHODS: A total of 133 healthy volunteers (67 men, 66 women) were randomly assigned to agomelatine (25 or 50 mg) or escitalopram (20 mg) or placebo for nine weeks. Sexual acceptability was evaluated by using the psychotropic-related sexual dysfunction questionnaire 5-items total score and sexual dysfunction relative to each sub-score (in 110 volunteers with sexual activity). Sexual dysfunction was evaluated at baseline and after two, five and eight weeks of treatment and one week after drug discontinuation. RESULTS: The psychotropic-related sexual dysfunction questionnaire 5-items total score was significantly lower in both agomelatine groups versus escitalopram at all visits (p < 0.01 to p < 0.0001) with no difference between agomelatine and placebo nor between both agomelatine doses. Similar results were observed after drug discontinuation. The total score was significantly higher in the escitalopram group than in the placebo group at each post-baseline visit (p < 0.01 to p < 0.001). Similar results were observed regardless of volunteers' gender. Compared to placebo, only escitalopram significantly impaired dysfunction relative to "delayed orgasm or ejaculation" (p < 0.01) and "absence of orgasm or ejaculation" (p < 0.05 to p < 0.01). The percentage of participants with a sexual dysfunction was higher in the escitalopram group than in agomelatine groups (p < 0.01 to p < 0.05) and placebo (p < 0.01). CONCLUSION: The study confirms the better sexual acceptability profile of agomelatine (25 or 50 mg) in healthy men and women, compared to escitalopram. TRIAL REGISTRATION NAME: Evaluation of the effect of agomelatine and escitalopram on emotions and motivation in healthy male and female volunteers. TRIAL REGISTRATION NUMBER: ISRCTN75872983.
Assuntos
Acetamidas/administração & dosagem , Citalopram/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Adulto , Método Duplo-Cego , Emoções/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Inquéritos e Questionários , Adulto JovemRESUMO
RATIONALE: Agomelatine is described as a novel and clinical effective antidepressant drug with melatonergic (MT(1)/MT(2)) agonist and 5-HT(2C) receptor antagonist properties. Previous studies suggest that modulation of neuronal plasticity and microtubule dynamics may be involved in the treatment of depression. OBJECTIVE: The present study investigated the effects of agomelatine on microtubular, synaptic and brain-derived neurotrophic factor (BDNF) proteins in selected rat brain regions. METHODS: Adult male rats received agomelatine (40 mg/kg i.p.) once a day for 22 days. The pro-cognitive effect of agomelatine was tested in the novel object recognition task and antidepressant activity in the forced swimming test. Microtubule dynamics markers, microtubule-associated protein type 2 (MAP-2), phosphorylated MAP-2, synaptic markers [synaptophysin, postsynaptic density-95 (PSD-95) and spinophilin] and BDNF were measured by Western blot in the hippocampus, amygdala and prefrontal cortex (PFC). RESULTS: Agomelatine exerted pro-cognitive and antidepressant activity and induced molecular changes in the brain areas examined. Agomelatine enhanced microtubule dynamics in the hippocampus and to a higher magnitude in the amygdala. By contrast, in the PFC, a decrease in microtubule dynamics was observed. Spinophilin (dendritic spines marker) was decreased, and BDNF increased in the hippocampus. Synaptophysin (presynaptic) and spinophilin were increased in the PFC and amygdala, while PSD-95 (postsynaptic marker) was increased in the amygdala, consistent with the phenomena of synaptic remodelling. CONCLUSIONS: Agomelatine modulates cytoskeletal microtubule dynamics and synaptic markers. This may play a role in its pharmacological behavioural effects and may result from the melatonergic agonist and 5-HT(2C) antagonist properties of the compound.
Assuntos
Acetamidas/farmacologia , Antidepressivos/farmacologia , Cognição/efeitos dos fármacos , Depressão/tratamento farmacológico , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Sinapses/metabolismoRESUMO
The novel melatonergic agonist/5-HT(2C) antagonist agomelatine displays robust antidepressant properties in humans and is active in pre-clinical models predictive of antidepressant effects. In this study, we investigated its potential influence on the locomotor hyperactivity displayed by olfactory bulbectomised rats, a putative measure of potential antidepressant activity. In addition, we compared the actions of agomelatine to those of melatonin and S32006, a selective antagonist at 5-HT(2C) receptors. Vehicle, agomelatine (10 and 50mg/kg), melatonin (10 and 50mg/kg), S32006 (0.16mg/kg to 10mg/kg) and the prototypical tricyclic antidepressant, imipramine (10mg/kg), were administered by intraperitoneal injection for 14days to male, Sprague-Dawley sham-operated and bulbectomised rats. In agreement with previous studies, imipramine was active in the model and both the lower and higher doses of agomelatine also significantly and markedly reversed the bulbectomy-induced hyperactivity to a level comparable to that seen in sham operated animals, in which agomelatine exerted no effect. Similarly the 5-HT(2C) antagonist, S32006, dose-dependently and significantly attenuated hyperactivity of bulbectomised animals, albeit with a maximal effect somewhat less marked than that of agomelatine. On the other hand, melatonin did not affect the locomotor behaviour of bulbectomised rats. The activity of agomelatine in the model is consistent with its known antidepressant properties in the clinic.
Assuntos
Acetamidas/farmacologia , Hipercinese/tratamento farmacológico , Indóis/farmacologia , Melatonina/farmacologia , Bulbo Olfatório/cirurgia , Piridinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Acetamidas/uso terapêutico , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Indóis/uso terapêutico , Masculino , Melatonina/uso terapêutico , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêuticoRESUMO
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. In agreement with our previous work, acute stress increases extracellular glutamate levels in the basolateral nucleus of the amygdala (BLA). Similarly, acute stress increases glutamate efflux in the central nucleus of the amygdala (CeA). In the hippocampus, acute stress increases glutamate efflux and elicits an oscillatory pattern of GABA efflux. Agomelatine administration (40mg/kg ip) prior to acute stress inhibited stress-mediated increases in glutamate efflux in the hippocampus, BLA and CeA. These results demonstrate that acute agomelatine administration effectively inhibits acute stress-mediated changes in extracellular glutamate in the rat hippocampus and amygdala. While acute stress did not modulate GABA efflux in these regions, agomelatine treatment induced an overall reduction of GABA levels in the hippocampus. These data suggest that agomelatine modulates amino acid efflux in limbic structures implicated in major depressive disorder.