RESUMEN
In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.
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Sistema Hipotálamo-Hipofisario , Receptores de Glucocorticoides , Femenino , Embarazo , Animales , Ratones , Sistema Hipotálamo-Hipofisario/metabolismo , Receptores de Glucocorticoides/metabolismo , Glucocorticoides/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , HomeostasisRESUMEN
Whether microRNAs (miRNAs) from plasma exosomes might be dysregulated in patients with depression, especially treatment-resistant depression (TRD), remains unclear, based on study of which novel biomarkers and therapeutic targets could be discovered. To this end, a small sample study was performed by isolation of plasma exosomes from patients with TRD diagnosed by Hamilton scale. In this study, 4 peripheral plasma samples from patients with TRD and 4 healthy controls were collected for extraction of plasma exosomes. Exosomal miRNAs were analyzed by miRNA sequencing, followed by image collection, expression difference analysis, target gene GO enrichment analysis, and KEGG pathway enrichment analysis. Compared with the healthy controls, 2 miRNAs in the plasma exosomes of patients with TRD showed significant differences in expression, among which has-miR-335-5p were significantly upregulated and has-miR-1292-3p were significantly downregulated. Go and KEGG analysis showed that dysregulated miRNAs affect postsynaptic density and axonogenesis as well as the signaling pathway of axon formation and cell growths. The identification of these miRNAs and their target genes may provide novel biomarkers for improving diagnosis accuracy and treatment effectiveness of TRD.
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Trastorno Depresivo Resistente al Tratamiento/genética , Exosomas/genética , MicroARNs/genética , Adolescente , Adulto , Anciano , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/patología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ARN/métodos , Adulto JovenRESUMEN
The pathogenesis of post-traumatic stress disorder (PTSD) remains largely unclear. A large body of evidence suggests that the abnormal level of serotonin (5-HT) is closely related to the onset of PTSD. Several reports reveal that nitric oxide (NO) affects extracellular 5-HT levels in various brain regions, but no consistent direction of change was found and the underlying mechanisms remain unknown. The most of serotonergic neurons in dorsal raphe nucleus (DRN), a major source of serotonergic input to the forebrain, co-expresses neuronal nitric oxide synthase (nNOS), a synthase derived nitric oxide (NO) in the central nervous system. Here, we found that the excessive expression of nNOS and thereby the high concentration of NO followed by single-prolonged stress (SPS) caused suppression of the activity of DRN 5-HT neurons, inducing PTSD-like phenotype including increased anxiety-like behaviors, enhanced contextual fear memory, and fear generalization. Our study uncovered an important role of DRN nNOS-NO pathway in the pathology of PTSD, which may contribute to new understanding of the molecular mechanism of PTSD.
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Conducta Animal/fisiología , Núcleo Dorsal del Rafe/fisiopatología , Óxido Nítrico Sintasa de Tipo I/metabolismo , Neuronas Serotoninérgicas/metabolismo , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico/fisiopatología , Animales , Ansiedad/fisiopatología , Ansiedad/psicología , Núcleo Dorsal del Rafe/enzimología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones Endogámicos C57BL , Actividad Motora/fisiología , Óxido Nítrico/metabolismo , Neuronas Serotoninérgicas/citología , Serotonina/metabolismo , Trastornos por Estrés Postraumático/metabolismo , Estrés Psicológico/psicologíaRESUMEN
Proparacaine (PPC) is a previously discovered topical anesthetic for ophthalmic optometry and surgery by blocking the central Nav1.3. In this study, we found that proparacaine hydrochloride (PPC-HCl) exerted an acute robust antiepileptic effect in pilocarpine-induced epilepsy mice. More importantly, chronic treatment with PPC-HCl totally terminated spontaneous recurrent seizure occurrence without significant toxicity. Chronic treatment with PPC-HCl did not cause obvious cytotoxicity, neuropsychiatric adverse effects, hepatotoxicity, cardiotoxicity, and even genotoxicity that evaluated by whole genome-scale transcriptomic analyses. Only when in a high dose (50 mg/kg), the QRS interval measured by electrocardiography was slightly prolonged, which was similar to the impact of levetiracetam. Nevertheless, to overcome this potential issue, we adopt a liposome encapsulation strategy that could alleviate cardiotoxicity and prepared a type of hydrogel containing PPC-HCl for sustained release. Implantation of thermosensitive chitosan-based hydrogel containing liposomal PPC-HCl into the subcutaneous tissue exerted immediate and long-lasting remission from spontaneous recurrent seizure in epileptic mice without affecting QRS interval. Therefore, this new liposomal hydrogel formulation of proparacaine could be developed as a transdermal patch for treating epilepsy, avoiding the severe toxicity after chronic treatment with current antiepileptic drugs in clinic.
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Anticonvulsivantes/uso terapéutico , Sistemas de Liberación de Medicamentos/métodos , Epilepsia/tratamiento farmacológico , Propoxicaína/uso terapéutico , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Electroencefalografía , Suspensión Trasera , Hidrogeles , Liposomas/administración & dosificación , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones Endogámicos C57BL , Prueba de Campo Abierto/efectos de los fármacos , Propoxicaína/administración & dosificación , Propoxicaína/efectos adversosRESUMEN
Sucrose preference test (SPT) is a most frequently applied method for measuring anhedonia, a core symptom of depression, in rodents. However, the method of SPT still remains problematic mainly due to the primitive, irregular, and inaccurate various types of home-made equipment in laboratories, causing imprecise, inconsistent, and variable results. To overcome this issue, we devised a novel method for automatic detection of anhedonia in mice using an electronic apparatus with its program for automated detecting the behavior of drinking of mice instead of manual weighing the water bottles. In this system, the liquid surface of the bottles was monitored electronically by infrared monitoring elements which were assembled beside the plane of the water surface and the information of times and duration of each drinking was collected to the principal machine. A corresponding computer program was written and installed in a computer connected to the principal machine for outputting and analyzing the data. This new method, based on the automated system, was sensitive, reliable, and adaptable for evaluation of stress- or drug-induced anhedonia, as well as taste preference and effects of addictive drugs. Extensive application of this automated apparatus for SPT would greatly improve and standardize the behavioral assessment method of anhedonia, being instrumental in novel antidepressant screening and depression researching.
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Anhedonia , Depresión/psicología , Anhedonia/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , SacarosaRESUMEN
In this study, a comprehensive model for suitable carrying capacity of resources and environment was proposed based on ecological footprint method. Using the spatiotemporal distribution data of land use in Chongqing Section of Three Gorges Reservoir Area from 2001 to 2016, the response changes of carrying capacity of resources and environment under the evolution of land use structure were investigated. The analytical results showed that the suitable carrying capacity of resources and environment in Chongqing decreased first and then increased. In the early stage of the Three Gorges Project, some districts and counties exhibited the phenomenon of suitable carrying capacity deficit, especially in the northeast of Chongqing. In the main urban area of Chongqing, the suitable carrying capacity was also mainly restricted by the ecological resources conditions, the deficit was getting worse with the increase of population density. In the later stage, by restoring ecology and improving the living and economic conditions, the phenomenon of deficit was gradually alleviated. These findings will provide some references for the protection of ecological environment and the development of social economy in Chongqing Section of the Three Gorges Reservoir Area.
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Conservación de los Recursos Naturales , ChinaRESUMEN
Anxiety disorders are associated with a high social burden worldwide. Recently, increasing evidence suggests that nuclear factor kappa B (NF-κB) has significant implications for psychiatric diseases, including anxiety and depressive disorders. However, the molecular mechanisms underlying the role of NF-κB in stress-induced anxiety behaviors are poorly understood. In this study, we show that chronic mild stress (CMS) and glucocorticoids dramatically increased the expression of NF-κB subunits p50 and p65, phosphorylation and acetylation of p65, and the level of nuclear p65 in vivo and in vitro, implicating activation of NF-κB signaling in chronic stress-induced pathological processes. Using the novelty-suppressed feeding (NSF) and elevated-plus maze (EPM) tests, we found that treatment with pyrrolidine dithiocarbamate (PDTC; intra-hippocampal infusion), an inhibitor of NF-κB, rescued the CMS- or glucocorticoid-induced anxiogenic behaviors in mice. Microinjection of PDTC into the hippocampus reversed CMS-induced up-regulation of neuronal nitric oxide synthase (nNOS), carboxy-terminal PDZ ligand of nNOS (CAPON), and dexamethasone-induced ras protein 1 (Dexras1) and dendritic spine loss of dentate gyrus (DG) granule cells. Moreover, over-expression of CAPON by infusing LV-CAPON-L-GFP into the hippocampus induced nNOS-Dexras1 interaction and anxiety-like behaviors, and inhibition of NF-κB by PDTC reduced the LV-CAPON-L-GFP-induced increases in nNOS-Dexras1 complex and anxiogenic-like effects in mice. These findings indicate that hippocampal NF-κB mediates anxiogenic behaviors, probably via regulating the association of nNOS-CAPON-Dexras1, and uncover a novel approach to the treatment of anxiety disorders.
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Ansiedad/etiología , Ansiedad/patología , Hipocampo/citología , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Dominios PDZ/fisiología , Estrés Psicológico/complicaciones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Animales Recién Nacidos , Antioxidantes/farmacología , Conducta Animal/efectos de los fármacos , Corticosterona/metabolismo , Corticosterona/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Proteínas Asociadas a Microtúbulos/metabolismo , Pirrolidinas/farmacología , Transducción de Señal/fisiología , Estrés Psicológico/patología , Tiocarbamatos/farmacología , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Proteínas ras/metabolismoRESUMEN
BACKGROUND: Neurological deficits of alcohol use disorder (AUD) have been attributed to dysfunctions of specific brain structures. Studies of alcoholic patients and chronic alcohol exposure animal models consistently identify reduced hippocampal mass and cogntive dysfunctions as a key alcohol-induced brain adaptation. However, the precise substrate of chronic alcohol exposure that leads to structural and functional impairments of the hippocampus is largely unknown. METHODS: Using a calorie-matched alcohol feeding method, we tested whether chronic alcohol exposure targets neural stem cells and neurogenesis in the adult hippocampus. The effect of alcohol on proliferation of neural stem cells as well as cell fate determination and survival of newborn cells was evaluated via bromodeoxyuridine pulse and chase methods. A retrovirus-mediated single-cell labeling method was used to determine the effect of alcohol on the morphological development and circuitry incorporation of individual hippocampal newborn neurons. Finally, novel object recognition (NOR) and Y-maze tests were performed to examine whether disrupted neurogenesis is associated with hippocampus-dependent functional deficits in alcohol-fed mice. RESULTS: Chronic alcohol exposure reduced proliferation of neural stem cells and survival rate of newborn neurons; however, the fate determination of newborn cells remained unaltered. Moreover, the dendritic spine density of newborn neurons significantly decreased in alcohol-fed mice. Impaired spine formation indicates that alcohol interfered the synaptic connectivity of newborn neurons with excitatory neurons originating from various areas of the brain. In the NOR test, alcohol-fed mice displayed deficits in the ability to discriminate the novel object. CONCLUSIONS: Our study revealed that chronic alcohol exposure disrupted multiple steps of neurogenesis, including the production and development of newborn neurons. In addition, chronic alcohol exposure altered connectivity of newborn neurons with other input neurons. Decreased neurogenesis and aberrant integration of newborn neurons into hippocampal networks are closely associated with deficits in hippocampus-dependent cognitive functions of alcohol-fed mice.
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Encéfalo/efectos de los fármacos , Trastornos del Conocimiento/inducido químicamente , Etanol/administración & dosificación , Etanol/farmacología , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/patología , Consumo de Bebidas Alcohólicas/patología , Consumo de Bebidas Alcohólicas/fisiopatología , Consumo de Bebidas Alcohólicas/psicología , Animales , Encéfalo/patología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/patología , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Células-Madre Neurales/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Major depressive disorder is a severe, life-threatening and highly prevalent psychiatric disorder. A high percentage of people suffering from depression are characterized by hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in plasma glucocorticoid (cortisol in human and corticosterone in rodent) elevations. Glucocorticoid is a critical molecule in the onset of pathology of depression. A simple, highly sensitive and specific method based on ultra-fast liquid chromatography-tandem mass spectrometry method has been developed for the quantitation of corticosterone in mouse plasma for the first time, which provides technical support for the high-throughput measurement for clinical determination of corticosterone in biological samples. Samples were spiked with methanol to precipitate the protein, and then chromatographed on an Agilent Zorbax Eclipse Plus C18 (100 × 2.1 mm,1.8 µm) column by linear gradient elution with methanol and 0.1% formic acid as the mobile phase within 5 min. The detection of corticosterone was performed on ultra-fast liquid chromatography-triple quadrupole tandem mass spectrometry in the positive ion. The ions [M + H](+) m/z 347.2 â m/z 311.1 for corticosterone and [M + H](+) m/z 363.2 â m/z 327.2 for hydrocortisone (internal standard) were used for quantitative determination. The lower quantification limit for corticosterone was 1 ng/mL. The validated method was successfully applied to the quantitation of corticosterone in mouse plasma.
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Cromatografía Líquida de Alta Presión/métodos , Corticosterona/sangre , Espectrometría de Masas en Tándem/métodos , Animales , Análisis de los Mínimos Cuadrados , Ratones , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Glucocorticoids (GCs) are steroidal hormones produced by the adrenal cortex. A physiological-level GCs have a crucial function in maintaining many cognitive processes, like cognition, memory, and mood, however, both insufficient and excessive GCs impair these functions. Although this phenomenon could be explained by the U-shape of GC effects, the underlying mechanisms are still not clear. Therefore, understanding the underlying mechanisms of GCs may provide insight into the treatments for cognitive and mood-related disorders. METHODS: Consecutive administration of corticosterone (CORT, 10 mg/kg, i.g.) proceeded for 28 days to mimic excessive GCs condition. Adrenalectomy (ADX) surgery was performed to ablate endogenous GCs in mice. Microinjection of 1 µL of Ad-mTERT-GFP virus into mouse hippocampus dentate gyrus (DG) and behavioral alterations in mice were observed 4 weeks later. RESULTS: Different concentrations of GCs were shown to affect the cell growth and development of neural stem cells (NSCs) in a U-shaped manner. The physiological level of GCs (0.01 µM) promoted NSC proliferation in vitro, while the stress level of GCs (10 µM) inhibited it. The glucocorticoid synthesis blocker metyrapone (100 mg/kg, i.p.) and ADX surgery both decreased the quantity and morphological development of doublecortin (DCX)-positive immature cells in the DG. The physiological level of GCs activated mineralocorticoid receptor and then promoted the production of telomerase reverse transcriptase (TERT); in contrast, the stress level of GCs activated glucocorticoid receptor and then reduced the expression of TERT. Overexpression of TERT by AD-mTERT-GFP reversed both chronic stresses- and ADX-induced deficiency of TERT and the proliferation and development of NSCs, chronic stresses-associated depressive symptoms, and ADX-associated learning and memory impairment. CONCLUSION: The bidirectional regulation of TERT by different GCs concentrations is a key mechanism mediating the U-shape of GC effects in modulation of hippocampal NSCs and associated brain function. Replenishment of TERT could be a common treatment strategy for GC dysfunction-associated diseases.
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Glucocorticoides , Células-Madre Neurales , Ratones , Animales , Glucocorticoides/farmacología , Glucocorticoides/metabolismo , Hipocampo/metabolismo , Corticosterona/farmacología , Células-Madre Neurales/metabolismo , Trastornos de la Memoria/metabolismoRESUMEN
The hippocampus is rich in both glucocorticoid receptor (GR) and neuronal nitric oxide synthase (nNOS). But the relationship between the two molecules under physiological states remains unrevealed. Here, we report that nNOS knockout mice display increased GR expression in the hippocampus. Both systemic administration of 7-Nitroindazole (7-NI), a selective nNOS activity inhibitor, and selective infusion of 7-NI into the hippocampus resulted in an increase in GR expression in the hippocampus. Moreover, KCl exposure, which can induce overexpression of nNOS, resulted in a decrease in GR protein level in cultured hippocampal neurons. Moreover, blockade of nNOS activity in the hippocampus leads to decreased corticosterone (CORT, glucocorticoids in rodents) concentration in the plasma and reduced corticotrophin-releasing factor expression in the hypothalamus. The results indicate that nNOS is an endogenous inhibitor of GR in the hippocampus and that nNOS in the hippocampus may participate in the modulation of Hypothalamic-Pituitary-Adrenal axis activity via GR.
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Hipocampo/enzimología , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/fisiología , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/biosíntesis , Animales , Inhibidores Enzimáticos/farmacología , Hipocampo/efectos de los fármacos , Indazoles/farmacología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones NoqueadosRESUMEN
The molecular mechanisms underlying the behavioral effects of glucocorticoids are poorly understood. We report here that hippocampal neuronal nitric oxide synthase (nNOS) is a crucial mediator. Chronic mild stress and glucocorticoids exposures caused hippocampal nNOS overexpression via activating mineralocorticoid receptor. In turn, hippocampal nNOS-derived nitric oxide (NO) significantly downregulated local glucocorticoid receptor expression through both soluble guanylate cyclase (sGC)/cGMP and peroxynitrite (ONOO(-))/extracellular signal-regulated kinase signal pathways, and therefore elevated hypothalamic corticotrophin-releasing factor, a peptide that governs the hypothalamic-pituitary-adrenal axis. More importantly, nNOS deletion or intrahippocampal nNOS inhibition and NO-cGMP signaling blockade (using NO scavenger or sGC inhibitor) prevented the corticosterone-induced behavioral modifications, suggesting that hippocampal nNOS is necessary for the role of glucocorticoids in mediating depressive behaviors. In addition, directly delivering ONOO(-) donor into hippocampus caused depressive-like behaviors. Our findings reveal a role of hippocampal nNOS in regulating the behavioral effects of glucocorticoids.
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Depresión/metabolismo , Regulación hacia Abajo/fisiología , Glucocorticoides/farmacología , Hipocampo/metabolismo , Óxido Nítrico Sintasa de Tipo I/fisiología , Receptores de Glucocorticoides/antagonistas & inhibidores , Estrés Psicológico/metabolismo , Animales , Células Cultivadas , Depresión/psicología , Regulación hacia Abajo/efectos de los fármacos , Glucocorticoides/metabolismo , Guanilato Ciclasa/fisiología , Hipocampo/efectos de los fármacos , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos ICR , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo I/deficiencia , Técnicas de Cultivo de Órganos , Ácido Peroxinitroso/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico/psicologíaRESUMEN
Telomere and telomerase alterations have been reported in mood disorders. However, the role of telomerase in depression remains unclear. Here we show that chronic mild stress (CMS) led to a significant decrease in telomerase reverse transcriptase (TERT) level and telomerase activity in the hippocampus. Treatment with antidepressant fluoxetine reversed the CMS-induced TERT and telomerase activity changes. Inhibiting telomerase by systemic administration (100 mg · kg(-1) · d(-1), i.p., for 14 d), intrahippocampal microinjection (0.7 µmol, 2 µl), or infusion (using an osmotic minipump, 0.134 µg/µl, 0.25 µl/h) of 3'-azido-deoxythymidine (AZT) resulted in depression-like behaviors and impaired hippocampal neurogenesis in mice. In contrast, overexpressing telomerase by intrahippocampal infusion of recombinant adenovirus vector expressing mouse TERT (Ad-mTERT-GFP) led to neurogenesis upregulation, produced antidepressant-like behaviors, and prevented the CMS-induced behavioral modifications. Disrupting neurogenesis in the dentate gyrus by X-irradiation (15 Gy) of a restricted region of mouse brain containing the hippocampus abolished the antidepressant-like effect of Ad-mTERT-GFP. Additionally, AZT had no effect on DNA polymerase activity and did not cause cell damage in vitro and in vivo. Microinjection of AZT into the subventricular zone of lateral ventricle (0.7 µmol, 2 µl) inhibited local neurogenesis but had no behavioral effect. These results suggest that hippocampal telomerase is involved in the modulation of depression-related behaviors, possibly by regulating adult neurogenesis.
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Trastorno Depresivo/enzimología , Hipocampo/enzimología , Neurogénesis/fisiología , Telomerasa/fisiología , Envejecimiento/patología , Envejecimiento/fisiología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Células Cultivadas , Trastorno Depresivo/genética , Trastorno Depresivo/patología , Modelos Animales de Enfermedad , Femenino , Hipocampo/fisiopatología , Ratones , Ratones Endogámicos C57BL , Neurogénesis/efectos de los fármacos , Neurogénesis/genética , Estrés Psicológico/enzimología , Estrés Psicológico/genética , Estrés Psicológico/patología , Telomerasa/antagonistas & inhibidores , Telomerasa/genéticaRESUMEN
Major depressive disorder (MDD) is one of the foremost causes of disability and premature death worldwide. Although the available antidepressants are effective and well tolerated, they also have many limitations. Therapeutic advances in developing a new drug's ultimate relation between MDD and chronobiology, which targets the circadian rhythm, led to a renewed focus on psychiatric disorders. In order to provide a critical analysis about antidepressant properties of agomelatine, a detailed PubMed (Medline), Scopus (Embase), Web of Science (Web of Knowledge), Cochrane Library, Google Scholar, and PsycInfo search was performed using the following keywords: melatonin analog, agomelatine, safety, efficacy, adverse effects, pharmacokinetics, pharmacodynamics, circadian rhythm, sleep disorders, neuroplasticity, MDD, bipolar disorder, anhedonia, anxiety, generalized anxiety disorder (GAD), and mood disorders. Agomelatine is a unique melatonin analog with antidepressant properties and a large therapeutic index that improves clinical safety. Published articles revealed that agomelatine is a melatonin receptors (MT1 and MT2) agonist and 5HT2C receptor antagonist. The effects receptors' on melatonin receptors enable the resynchronization of irregular circadian rhythms with beneficial effects on sleep architectures. In this way, agomelatine is accredited for its unique mode of action, which helps to exert antidepressant effects and resynchronize the sleep-wake cycle. To sum up, an agomelatine has not only antidepressant properties but also has anxiolytic effects.
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Trastorno Depresivo Mayor , Melatonina , Acetamidas , Antidepresivos/efectos adversos , Trastorno Depresivo Mayor/inducido químicamente , Trastorno Depresivo Mayor/tratamiento farmacológico , Humanos , Melatonina/farmacología , Melatonina/uso terapéutico , Naftalenos , Receptores de Melatonina/uso terapéuticoRESUMEN
Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.
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Antidepresivos , Trastorno Depresivo Mayor , Núcleo Dorsal del Rafe , Diseño de Fármacos , Óxido Nítrico Sintasa de Tipo I , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Animales , Ratones , Antidepresivos/química , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Núcleo Dorsal del Rafe/efectos de los fármacos , Núcleo Dorsal del Rafe/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismoRESUMEN
AIMS: This study aimed to explore the pathomechanism of a mutation on the leucine-rich glioma inactivated 1 gene (LGI1) identified in a family having autosomal dominant lateral temporal lobe epilepsy (ADLTE), using a precise knock-in mouse model. METHODS AND RESULTS: A novel LGI1 mutation, c.152A>G; p. Asp51Gly, was identified by whole exome sequencing in a Chinese family with ADLTE. The pathomechanism of the mutation was explored by generating Lgi1D51G knock-in mice that precisely phenocopied the epileptic symptoms of human patients. The Lgi1D51G/D51G mice showed spontaneous recurrent generalized seizures and premature death. The Lgi1D51G/+ mice had partial epilepsy, with half of them displaying epileptiform discharges on electroencephalography. They also showed enhanced sensitivity to the convulsant agent pentylenetetrazole. Mechanistically, the secretion of Lgi1 was impaired in the brain of the D51G knock-in mice and the protein level was drastically reduced. Moreover, the antiepileptic drugs, carbamazepine, oxcarbazepine, and sodium valproate, could prolong the survival time of Lgi1D51G/D51G mice, and oxcarbazepine appeared to be the most effective. CONCLUSIONS: We identified a novel epilepsy-causing mutation of LGI1 in humans. The Lgi1D51G/+ mouse model, precisely phenocopying epileptic symptoms of human patients, could be a useful tool in future studies on the pathogenesis and potential therapies for epilepsy.
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Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/genética , Animales , Niño , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , LinajeRESUMEN
Increasing evidence suggests that 5-HT(1A) receptor (5-HT(1A)R) is implicated in anxiety disorders. However, the mechanism underlying the role of 5-HT(1A)R in these diseases remains unknown. Here, we show that 5-HT(1A)R-selective agonist 8-OH-DPAT and selective serotonin reuptake inhibitor (SSRI) fluoxetine downregulated hippocampal neuronal nitric oxide synthase (nNOS) expression, whereas 5-HT(1A)R-selective antagonist NAN-190 upregulated hippocampal nNOS expression. By assessing anxiety-related behaviors using the novelty suppressed feeding, open-field, and elevated plus maze tests, we show that mice lacking nNOS gene [knock-out (KO)] or treated with nNOS-selective inhibitor 7-nitroindazole (7-NI; i.p., 30 mg/kg/d for 28 d; or intrahippocampal microinjection, 16.31 microg/1.0 microl) displayed an anxiolytic-like phenotype, implicating nNOS in anxiety. We also show that, in wild-type (WT) mice, administrations of 8-OH-DPAT (i.p., 0.1 mg/kg/d) or fluoxetine (i.p., 10 mg/kg/d) for 28 d caused anxiolytic-like effects, whereas NAN-190 (i.p., 0.3 mg/kg/d for 28 d) caused anxiogenic-like effects. In KO mice, however, these drugs were ineffective. Moreover, intrahippocampal infusion of 8-OH-DPAT (45.963 microg/100 microl) using 14 d osmotic minipump produced anxiolytic effects. Intrahippocampal microinjection of 7-NI (16.31 microg/1.0 microl) abolished the anxiogenic-like effects of intrahippocampal NAN-190 (4.74 microg/1.0 microl). Additionally, NAN-190 decreased and 8-OH-DPAT increased phosphorylated cAMP response element-binding protein (CREB) levels in WT mice but not in KO mice. Blockade of hippocampal CREB phosphorylation by microinjection of H89 (5.19 microg/1.0 microl), a PKA (protein kinase A) inhibitor, abolished the anxiolytic-like effects of 7-NI (i.p., 30 mg/kg/d for 21 d). These findings indicate that both hippocampal nNOS and CREB activity mediate the anxiolytic effects of 5-HT(1A)R agonists and SSRIs.
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Trastornos de Ansiedad/enzimología , Trastornos de Ansiedad/fisiopatología , Óxido Nítrico Sintasa de Tipo I/fisiología , Receptor de Serotonina 5-HT1A/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Animales Recién Nacidos , Trastornos de Ansiedad/inducido químicamente , Trastornos de Ansiedad/tratamiento farmacológico , Proteína de Unión a CREB/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Conducta Exploratoria/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Fluoxetina/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Indazoles/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo I/deficiencia , Fosforilación/efectos de los fármacos , Piperazinas/uso terapéutico , Tiempo de Reacción/efectos de los fármacos , Antagonistas de la Serotonina/uso terapéutico , Agonistas de Receptores de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Factores de TiempoRESUMEN
It has been demonstrated that neuronal nitric oxide synthase (nNOS) negatively regulates adult neurogenesis. However, the cellular and molecular mechanisms underlying are poorly understood. Here, we show that nNOS from neural stem cells (NSCs) and from neurons play opposite role in regulating neurogenesis. The NSCs treated with nNOS inhibitor N(5)-(1-imino-3-butenyl)-L- ornithine (L-VNIO) or nNOS gene deletion exhibited significantly decreased proliferation and neuronal differentiation, indicating that NSCs-derived nNOS is essential for neurogenesis. The NSCs cocultured with neurons displayed a significantly decreased proliferation, and deleting nNOS gene in neurons or scavenging extracellular nitric oxide (NO) abolished the effects of coculture, suggesting that neurons-derived nNOS, a source of exogenous NO for NSCs, exerts a negative control on neurogenesis. Indeed, the NSCs exposed to NO donor DETA/NONOate displayed decreased proliferation and neuronal differentiation. The bidirectional regulation of neurogenesis by NSCs- and neurons-derived nNOS is probably related to their distinct subcellular localizations, mainly in nuclei for NSCs and in cytoplasm for neurons. Both L-VNIO and DETA/NONOate inhibited telomerase activity and proliferation in wild-type (WT) but not in nNOS(-/-) NSCs, suggesting a nNOS-telomerase signaling in neurogenesis. The NSCs exposed to DETA/NONOate exhibited reduced cAMP response element binding protein (CREB) phosphorylation, nNOS expression, and proliferation. The effects of DETA/NONOate were reversed by forskolin, an activator of CREB signaling. Moreover, disrupting CREB phosphorylation by H-89 or LV-CREB133-GFP simulated the effects of DETA/NONOate, and inhibited telomerase activity. Thus, we conclude that NSCs-derived nNOS stimulates neurogenesis via activating telomerase, whereas neurons-derived nNOS represses neurogenesis by supplying exogenous NO that hinders CREB activation, in turn, reduces nNOS expression in NSCs.
Asunto(s)
Células-Madre Neurales/enzimología , Neurogénesis/fisiología , Neuronas/enzimología , Óxido Nítrico Sintasa de Tipo I/metabolismo , Animales , Western Blotting , Proliferación Celular , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Masculino , Ratones , Modelos Biológicos , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Neurogénesis/genética , Neuronas/citología , Neuronas/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , Óxidos de Nitrógeno/metabolismo , Telomerasa/metabolismoRESUMEN
Autism spectrum disorder (ASD) is a sort of mental disorder marked by deficits in cognitive and communication abilities. To date no effective cure for this pernicious disease has been available. Valproic acid (VPA) is a broad-spectrum, antiepileptic drug, and it is also a potent teratogen. Epidemiological studies have shown that children exposed to VPA are at higher risk for ASD during the first trimester of their gestational development. Several animal and human studies have demonstrated important behavioral impairments and morphological changes in the brain following VPA treatment. However, the mechanism of VPA exposure-induced ASD remains unclear. Several factors are involved in the pathological phase of ASD, including aberrant excitation/inhibition of synaptic transmission, neuroinflammation, diminished neurogenesis, oxidative stress, etc. In this review, we aim to outline the current knowledge of the critical pathophysiological mechanisms underlying VPA exposure-induced ASD. This review will give insight toward understanding the complex nature of VPA-induced neuronal toxicity and exploring a new path toward the development of novel pharmacological treatment against ASD.
Asunto(s)
Anticonvulsivantes/toxicidad , Trastorno del Espectro Autista/inducido químicamente , Síndromes de Neurotoxicidad/patología , Ácido Valproico/toxicidad , Animales , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/psicología , Femenino , Humanos , Síndromes de Neurotoxicidad/epidemiología , Síndromes de Neurotoxicidad/psicología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ácido Valproico/efectos adversos , Ácido Valproico/uso terapéuticoRESUMEN
The gut microbiota is composed of a large number of microbes, usually regarded as commensal bacteria. It has become gradually clear that gastrointestinal microbiota affects gut pathophysiology and the central nervous system (CNS) function by modulating the signaling pathways of the microbiota-gut-brain (MGB) axis. This bidirectional MGB axis communication primarily acts through neuroendocrine, neuroimmune, and autonomic nervous systems (ANS) mechanisms. Accumulating evidence reveals that gut microbiota interacts with the host brain, and its modulation may play a critical role in the pathology of neuropsychiatric disorders. Recently, neuroscience research has established the significance of gut microbiota in the development of brain systems that are essential to stress-related behaviors, including depression and anxiety. Application of modulators of the MGB, such as psychobiotics (e.g., probiotics), prebiotics, and specific diets, may be a promising therapeutic approach for neuropsychiatric disorders. The present review article primarily focuses on the relevant features of the disturbances of the MGB axis in the pathophysiology of neuropsychiatric disorders and its potential mechanisms.