RESUMO
Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age.
Assuntos
Envelhecimento , Proteínas Quinases Dependentes de AMP Cíclico , Dieta Cetogênica , Potenciação de Longa Duração , Memória , Proteoma , Transdução de Sinais , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Dieta Cetogênica/métodos , Proteoma/metabolismo , Camundongos , Masculino , Memória/fisiologia , Potenciação de Longa Duração/fisiologia , Camundongos Endogâmicos C57BL , Hipocampo/metabolismo , Sinapses/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Plasticidade Neuronal/fisiologia , FosforilaçãoRESUMO
Introducción y objetivo: Demostrar el valor del plano axial del complejo posterior, como apoyo a la detección antenatal de sintelencefalia, variante de holoprosencefalia. Método: Se incluyeron todas las pacientes con diagnóstico de sintelencefalia evaluadas desde el año 2008. En todos los casos se consignaron los datos clínicos, de neurosonografía (NSG), de resonancia magnética (RM) y genética. Resultados: Cuatro casos fueron diagnosticados en el segundo trimestre y en todos se realizó estudio genético y RM. Tres tuvieron en su evolución anomalías extra-SNC y dos de ellos alteraciones cromosómicas, una de ellas incompatible con la vida extrauterina. Lo hallazgos descritos en neuroimagen para esta afección fueron detectados en la NSG, con una excelente correlación con RM, ya fuera esta última realizada en periodo fetal o posnatal. Conclusión: El diagnóstico prenatal de variantes de holoprosencefalia es difícil, considerando la existencia de una fusión medial más acotada que en las formas clásicas. El presente estudio demuestra la utilidad del plano del complejo posterior para la sospecha diagnóstica de sintelencefalia.
Introduction and objective: To demonstrate the value of the axial plane of the posterior complex, as a clue for the antenatal detection of synthelencephaly, a variant of holoprosencephaly. Method: All patients diagnosed with syntelencephaly evaluated since 2008 were included. In all cases, clinical, neurosonography (NSG), magnetic resonance imaging (MRI) and genetic data were recorded. Results: Four cases were diagnosed in the second trimester and in all of them a genetic study and MRI were performed. Three had extra-CNS anomalies in their evolution and two of them chromosomal anomalies, one of them incompatible with extrauterine life. Neuroimaging findings described for this condition were detected by NSG, with an excellent correlation with MRI, whether the latter was performed in the fetal or postnatal period. Conclusion: The prenatal diagnosis of holoprosencephaly variants is difficult, considering the existence of a more limited medial fusion than in the classical forms. The present study demonstrates the usefulness of the posterior complex plane for the diagnostic suspicion of synthelencephaly.
Assuntos
Humanos , Feminino , Adulto , Adulto Jovem , Holoprosencefalia/diagnóstico por imagem , Gravidez em Diabéticas , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Holoprosencefalia/complicaçõesRESUMO
Objetivo: Reportar el resultado a largo plazo de una serie de fetos con agenesia del septum pellucidum aislada (ASP), con medición de su quiasma óptico mediante neurosonografía fetal (NSG). Método: Se incluyeron todas las pacientes con ASP y NSG evaluadas desde el año 2008 a la fecha y con seguimiento hasta su edad escolar. En todos los casos se consignaron los datos clínicos de NSG y de resonancia magnética (RM), cuando esta se realizó. Se entrevistó telefónicamente a los padres. Resultados: Nueve pacientes cumplieron los criterios: cuatro con displasia septo-óptica (DSO) (rango de seguimiento: 5-14 años) y cinco sin DSO (rango de seguimiento: 7-10 años). Un décimo caso se excluyó por tener solo 6 meses de seguimiento. Ninguna de las ASP tuvo otra anomalía detectada en su seguimiento. Ninguno de los casos con DSO tuvo alteración del tamaño de su quiasma óptico en la NSG ni anormalidad en la vía óptica en la RM. Conclusiones: En nuestra población, el riesgo residual de DSO frente a ASP es del 44,4%. En el seguimiento, nuestra definición de ASP por NSG no tuvo falsos negativos con relación a otras anomalías de aparición posnatal, a excepción de la DSO.
Objective: To report the long-term outcome of a series of fetuses with isolated septum pellucidum agenesis (ASP) with measurement of their optic chiasm by fetal neurosonography (NSG). Method: All patients with ASP and NSG evaluated from 2008 to date and with follow-up until their school age were included. In all cases, clinical, NSG and magnetic resonance imaging (MRI) data were recorded. Parents were interviewed by telephone. Results: Nine patients met the criteria: four with septo-optic dysplasia (SOD) (follow-up range: 5-14 years) and five without SOD (follow-up range: 7-10 years). A tenth case was excluded because only 6 months of follow-up. None of the ASP cases had another anomaly detected in their follow-up. None of the cases with DSO had anomaly of the size of their optic chiasm on NSG or abnormality in the optical pathway in the MRI. Conclusions: In our population, the residual risk of DSO versus ASP is 44.4%. At follow-up, our NSG definition of ASP had no false negatives in relation to other postnatal-onset anomalies, except for SOD.
Assuntos
Humanos , Masculino , Feminino , Gravidez , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Adulto Jovem , Quiasma Óptico/diagnóstico por imagem , Septo Pelúcido/anormalidades , Septo Pelúcido/diagnóstico por imagem , Displasia Septo-Óptica/diagnóstico por imagem , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Seguimentos , Ultrassonografia Pré-Natal , FetoRESUMO
Introducción: Los quistes interhemisféricos asociados a agenesia del cuerpo calloso constituyen un grupo infrecuente y heterogéneo de anomalías del SNC. Objetivo: Reportar nuestra experiencia en quistes interhemisféricos asociados a agenesia del cuerpo calloso (QIH/ACC), haciendo énfasis en sus características en la neurosonografía (NSG), su comparación con la resonancia magnética (RM) y su evolución clínica posterior. Método: Se incluyeron todas las pacientes con QIH/ACC evaluadas desde el año 2008. En todos los casos se consignaron los datos clínicos, de NSG y de RM cuando se realizó. Se entrevistó telefónicamente a los padres. Resultados: Fueron seleccionados 9 casos con QIH/ACC. De ellos, 5 fueron quistes tipo 1, 3 tuvieron anomalías asociadas y en los 3 hubo una anomalía genética patogénica. Cuatro casos fueron quistes tipo 2, 3 de ellos con un patrón NSG sugerente de síndrome de Aicardi. Hubo una excelente correlación entre NSG y RM, ya fuera esta última realizada ante- o posnatal, particularmente con relación a las malformaciones del desarrollo cortical asociadas al QIH/ACC. Conclusiones: En comparación con la RM y el resultado final, hubo alta concordancia con lo diagnosticado en la NSG, en especial en cuanto a malformaciones del desarrollo cortical asociadas, lo que añade valor al método diagnóstico que ofrecemos a nuestra población consultante.
Background: Callosal agenesis associated with interhemispheric cysts correspond to a rare and heterogenous group of CNS anomalies. Objective: To report our experience in interhemispheric cysts associated with agenesis of the corpus callosum (QIH/ACC), emphasizing its characteristics in neurosonography (NSG), its comparison with magnetic resonance imaging (MRI) and its subsequent clinical evolution. Method: All patients with QIH/ACC evaluated since 2008 were included. In all cases, clinical, NSG and MRI data were recorded when performed. The parents were interviewed by telephone. Results: A total of 9 cases were selected with QIH/ACC. 5 cases were type 1 cysts, 3 of them had associated abnormalities and in all 3 there was a pathogenic genetic anomaly. 4 cases were type 2 cysts, 3 of them with an NSG pattern suggestive of Aicardi syndrome. There was an excellent correlation between NSG and MRI, either before or postnatally, particularly in relation to cortical developmental malformations associated with QIH/ACC. Conclusions: Compared to MRI and the final result, there was high agreement with what was diagnosed in NSG, especially in what corresponds to associated cortical developmental malformations, which adds value to the diagnostic method we offer to our consulting population.
Assuntos
Humanos , Masculino , Feminino , Gravidez , Cistos/diagnóstico por imagem , Agenesia do Corpo Caloso/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia Pré-Natal , Síndrome de AicardiRESUMO
OBJECTIVES: To assess the feasibility of identifying fetal brain structures and anatomic landmarks included in the anterior complex (AC) and posterior complex (PC), as well as the proximal hemisphere (PH). METHODS: This was a prospective observational multicenter study of healthy pregnant women evaluated by ultrasound screening at 24 to 36 + 6 weeks' gestation. Six physicians performed transabdominal ultrasound, to obtain the planes required to visualize the AC, PC, and PH. Blind analysis by an expert and non-expert operator in fetal neurosonography was used to assess the structures included in each plane view. RESULTS: In the population studied (n=366), structure detection rates for AC were over 95â¯%, with an agreement of 96â¯% when comparing expert and non-expert examiners. Visualization of the corpus callosum crossing the midline was detected in over 97 and 96â¯% of cases for the AC and PC, respectively, with an agreement of over 96â¯%. The PH plane, particularly through the posterior access via the mastoid fontanelle, enabled visualization of the proximal anatomical structures in almost 95â¯% of cases. Detection of the corpus callosum through the AC and PC, both proximal/distal germinal matrix (AC) and proximal Sylvian fissure through the anterior access (PH) in the 24-25 + 6, 26-31 + 6 and 32-36 + 6 weeks' gestation groups were successful in over 96â¯% of cases with high level of agreement. CONCLUSIONS: Inclusion of AC, PC, and PH later in pregnancy proves feasible with a high level of agreement between both expert and non-expert operators.
Assuntos
Encéfalo , Ultrassonografia Pré-Natal , Gravidez , Feminino , Humanos , Estudos de Viabilidade , Ultrassonografia , Idade Gestacional , Encéfalo/diagnóstico por imagemRESUMO
Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol-requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an 5xFAD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the AD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.
Assuntos
Doença de Alzheimer , Animais , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Doença de Alzheimer/metabolismo , Estresse do Retículo Endoplasmático/genética , Camundongos Transgênicos , Proteômica , Proteostase/genética , Transdução de Sinais/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas/genéticaRESUMO
Age is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities in humans, primates, rodents, and invertebrates. Necroptosis mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here, we show that the loss of the necroptotic effector Mlkl was sufficient to delay age-associated axonal degeneration and neuroinflammation, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis targeting RIPK3 in aged mice, reverted structural and functional hippocampal impairment, both at the electrophysiological and behavioral level. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including a subclass of molecular biofunctions associated with brain rejuvenation, such as long-term potentiation and synaptic plasticity. Our results demonstrate that necroptosis contributes to age-dependent brain degeneration, disturbing hippocampal neuronal connectivity, and cognitive function. Therefore, necroptosis inhibition constitutes a potential geroprotective strategy to treat age-related disabilities associated with memory impairment and cognitive decline.
Assuntos
Necroptose , Doenças Neurodegenerativas , Humanos , Camundongos , Animais , Idoso , Proteômica , Rejuvenescimento , Envelhecimento/fisiologia , Encéfalo , Transtornos da MemóriaRESUMO
Resumen Objetivo: Describir y analizar los hallazgos ecográficos en 97 fetos portadores de síndrome de Down (SD) confirmado. Método: Se incluyeron todas las gestantes con diagnóstico prenatal de SD de nuestro centro, realizado por cariograma o reacción en cadena de la polimerasa cuantitativa fluorescente para aneuploidía. Se analizaron los informes genéticos y ecográficos, y se realizó un seguimiento posnatal. Resultados: De los 97 casos de SD, el 73% de los diagnósticos fueron entre las 11 y 14 semanas. El promedio de edad de las madres fue de 35,7 años. El 83% de los fetos con SD, evaluados a las 11-14 semanas, tuvieron una translucencia nucal ≥ 3,5 mm. Del total de los casos analizados, el 33% fueron portadores de una cardiopatía congénita, correspondiendo el 58% de estas a defectos mayores, principalmente anomalías del tabique auriculoventricular. Un 7,6% de los casos terminaron como mortinato, principalmente durante el tercer trimestre. Conclusiones: El ultrasonido es una herramienta muy sensible para la sospecha prenatal de SD y la detección de sus anomalías asociadas. Consideramos que la información aportada será útil para programar estrategias de pesquisa, organizar el control perinatal y precisar el consejo a los padres de fetos portadores de esta condición.
Abstract Objective: To describe and analyze the ultrasound findings in 97 fetuses with confirmed Down syndrome (DS). Method: All pregnant women with prenatal diagnosis of DS in our center, performed by karyotype or quantitative fluorescent polymerase chain reaction for aneuploidy, were included. Genetic and ultrasound reports were analyzed, as well as postnatal follow-up. Results: Of the 97 cases of DS, 73% of the diagnoses were between 11-14 weeks. The average age of the mothers was 35.7 years. 83% of our fetuses with DS, evaluated between 11-14 weeks, had a nuchal translucency ≥ 3.5 mm. Of the total of the fetuses analyzed, 33% were carriers of congenital heart disease, 58% of these correspond to a major defect, mainly anomalies of the atrioventricular septum. 7.6% of cases ended as stillbirth, mainly during the third trimester. Conclusions: Ultrasound is a very sensitive tool for prenatal suspicion of DS and the detection of its associated abnormalities. We believe that the information provided will be useful to program screening strategies, organize perinatal control and to counselling parents of fetuses carrying this condition.
Assuntos
Humanos , Feminino , Gravidez , Recém-Nascido , Ultrassonografia Pré-Natal/métodos , Síndrome de Down/genética , Síndrome de Down/diagnóstico por imagem , Doenças Fetais/genética , Doenças Fetais/diagnóstico por imagem , Fenótipo , Estudos Transversais , Estudos Retrospectivos , Seguimentos , Medição da Translucência Nucal , Mortalidade Fetal , Feto/anormalidades , Cardiopatias Congênitas/diagnóstico por imagemRESUMO
OBJETIVO: Analizar la implementación de la prueba rápida de reacción en cadena de la polimerasa cuantitativa y fluorescente (QF-PCR) para la detección de aneuploidías. MÉTODO: Se incluyeron todas las pacientes que se realizaron una QF-PCR entre septiembre de 2017 y mayo de 2021. En todos los casos se consignaron los datos clínicos, ecográficos y de laboratorio, y se efectuó un seguimiento de quienes se realizaron además cariograma y su resultado fue normal. RESULTADOS: Se realizaron 213 procedimientos invasivos genéticos prenatales, siendo 72 para detección rápida de aneuploidía mediante QF-PCR. El promedio de edad de las madres con QF-PCR fue de 37 años y 48 pacientes (67%) tenían menos de 15 semanas de gestación. La QF-PCR demostró aneuploidía de los cromosomas 18, 13 y de triploidía en 21 de 49 casos informados como anormales. De los 22 casos sin sugerencia de alteración, 17 accedieron a proseguir el estudio con cariotipo, que resultó anormal en 6 casos. Hubo 4 casos de discordancia entre la QF-PCR y el cariotipo, que pudo afectar el manejo clínico de la gestación. En 25/72 casos (34,7%) la aneuploidía era letal. CONCLUSIONES: Considerando la necesidad de tener un diagnóstico rápido, pero también completo y que permita un consejo genético apropiado, debería integrarse la QF-PCR a un protocolo de diagnóstico que considere variables clínicas y ecográficas.
OBJECTIVE: To analyze the performance of QF-PCR test for the detection of aneuploidies. METHOD: All patients who underwent QF-PCR from September 2017 to May 2021, were included. Clinical, ultrasound and laboratory data were recorded in all cases, as well as follow-up of the cases, including those performing karyotype and the result was normal. RESULTS: 213 prenatal genetic invasive procedures were performed in the study period, 72 for rapid detection of aneuploidy by QF-PCR. 48 patients (67%) were less than 15 weeks at the time of ultrasound diagnosis. The QF-PCR test demonstrated aneuploidy of chromosomes 18, 13, and triploidy in 21/49 cases reported as abnormal. Of the cases without suggestion of alteration (22), 17 agreed to continue the study with a karyotype, which was abnormal in 6 cases. There were 4 cases of discrepancy between QF-PCR and karyotype, which could affect the clinical management of pregnancy. 25/72 cases (34. 7%) corresponded to lethal aneuploidy. CONCLUSIONS: Our results justify the use of QF-PCR. Considering the need to have a rapid diagnosis, but also complete and that allows appropriate genetic counseling, it is that QF-PCR should be integrated into a protocol that considers clinical and ultrasound variables.
Assuntos
Humanos , Feminino , Gravidez , Adulto , Diagnóstico Pré-Natal/métodos , Reação em Cadeia da Polimerase/métodos , Aneuploidia , Aberrações Cromossômicas , Análise Citogenética , Aconselhamento GenéticoRESUMO
Alzheimer's disease (AD) is a major adult-onset neurodegenerative condition with no available treatment. Compelling reports point amyloid-ß (Aß) as the main etiologic agent that triggers AD. Although there is extensive evidence of detrimental crosstalk between Aß and microglia that contributes to neuroinflammation in AD, the exact mechanism leading to neuron death remains unknown. Using postmortem human AD brain tissue, we show that Aß pathology is associated with the necroptosis effector pMLKL. Moreover, we found that the burden of Aß oligomers (Aßo) correlates with the expression of key markers of necroptosis activation. Additionally, inhibition of necroptosis by pharmacological or genetic means, reduce neurodegeneration and memory impairment triggered by Aßo in mice. Since microglial activation is emerging as a central driver for AD pathogenesis, we then tested the contribution of microglia to the mechanism of Aßo-mediated necroptosis activation in neurons. Using an in vitro model, we show that conditioned medium from Aßo-stimulated microglia elicited necroptosis in neurons through activation of TNF-α signaling, triggering extensive neurodegeneration. Notably, necroptosis inhibition provided significant neuronal protection. Together, these findings suggest that Aßo-mediated microglia stimulation in AD contributes to necroptosis activation in neurons and neurodegeneration. As necroptosis is a druggable degenerative mechanism, our findings might have important therapeutic implications to prevent the progression of AD.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Transtornos da Memória/patologia , Camundongos , Microglia/patologia , NecroptoseRESUMO
Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3C57Y has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.
Assuntos
Deficiências do Desenvolvimento/genética , Retículo Endoplasmático/metabolismo , Isomerases de Dissulfetos de Proteínas/genética , Proteostase , Adolescente , Adulto , Animais , Axônios/metabolismo , Axônios/patologia , Adesão Celular , Células Cultivadas , Criança , Citoesqueleto/metabolismo , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Integrinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Crescimento Neuronal , Plasticidade Neuronal , Linhagem , Isomerases de Dissulfetos de Proteínas/metabolismo , Peixe-ZebraRESUMO
A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a-o) and (2-{4-[3-(1H-3-indolyl)-propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a-l) were synthesized and evaluated as novel multitarget ligands towards dopamine D2 receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 ± 0.82 nM, and 13c, Ki = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D2 ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D2 receptor in the nanomolar range (7n: Ki = 307 ± 6 nM and 7m: Ki = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D2 receptor (D2/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure-activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q2 = 0.625, 0.523 for CoMFA and CoMSIA and r2ncv = 0.967, 0.959 for CoMFA and CoMSIA, respectively).
Assuntos
Bioensaio/métodos , Receptores de Dopamina D2/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Receptores de Dopamina D2/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Relação Estrutura-AtividadeRESUMO
Zebrafish is becoming a popular animal model in neuropharmacology and drug discovery, mainly due to its ease of handling and low costs involved in maintenance and experimental work. This animal displays a series of complex behaviours that makes it useful for assessing the effects of psychoactive drugs. Here, adult zebrafish were used for assessment of the anxiolytic and anti-addictive properties of UFR2709, a nicotinic receptor (nAChR) antagonist, using two behavioural paradigms to test for addiction, the novel tank diving test to assess anxiety and the conditioned place preference (CPP). Furthermore, the expression of nAChR subunits α4 and α7 was measured in the zebrafish brain. The results show that UFR2709 exhibits an anxiolytic effect on zebrafish and blocks the effect evoked by nicotine on CPP. Moreover, UFR2709 significantly decreased the expression of α4 nicotinic receptor subunit. This indicates that UFR2709 might be a useful drug for the treatment of nicotine addiction.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Benzoatos/farmacologia , Nicotina/antagonistas & inibidores , Antagonistas Nicotínicos/farmacologia , Pirrolidinas/farmacologia , Receptores Nicotínicos/metabolismo , Recompensa , Animais , Ansiedade/induzido quimicamente , Modelos Animais de Doenças , Nicotina/administração & dosagem , Receptores Nicotínicos/genética , Natação , Peixe-ZebraRESUMO
OBJECTIVE: To introduce visualization of the germinal matrix (GM), external angle of the frontal horn, and periventricular white matter while evaluating the anterior complex (AC) during basic ultrasound assessment of the fetal brain. CASE PRESENTATIONS: This is a retrospective observational study of healthy women with singleton pregnancies, with no increased risk of fetal central nervous system anomalies, attending routine ultrasound screening at 20-32 weeks' gestation. Seventeen cases are presented in which an abnormal aspect of the GM or external angle of the frontal horn or periventricular white matter on AC evaluation has allowed a prenatal diagnosis of peri-intraventricular hemorrhage, subependymal cysts, connatal cysts, periventricular venous hemorrhagic infarction, and white matter injury. CONCLUSION: An extended AC evaluation could significantly improve the -diagnosis of hemorrhagic/cystic/hypoxic-ischemic lesions during the performance of a basic ultrasound study of the fetal brain.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/embriologia , Ultrassonografia Pré-Natal , Encéfalo/anormalidades , Cistos do Sistema Nervoso Central/diagnóstico por imagem , Cistos do Sistema Nervoso Central/embriologia , Hemorragia Cerebral Intraventricular/diagnóstico por imagem , Hemorragia Cerebral Intraventricular/embriologia , Ventrículos Cerebrais/irrigação sanguínea , Ventrículos Cerebrais/diagnóstico por imagem , Ventrículos Cerebrais/embriologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez , Estudos RetrospectivosRESUMO
OBJECTIVE: To assess the feasibility of identifying structures included in anterior complex (AC) and posterior complex (PC), as well as a series of anatomic landmarks that could help to demonstrate the integrity of the cerebral proximal hemisphere (PH). METHODS: This was a prospective observational multicenter study of healthy pregnant women attending routine ultrasound screening at 20 + 0 to 33 + 6 weeks' gestation. Six physicians performed transabdominal (TA) ultrasound, in order to obtain the planes required to visualize the AC, PC, and PH. Blind analysis by a nonexpert and two experts in fetal neurosonography was used to assess the structures included in each plane view. RESULTS: In the population studied (n = 747), detection of the structure rates for AC, PC, and proximal hemisphere was of 94%, 93%, and 96%, respectively, with an agreement of 97%, 94%, and 98% when comparing an expert and a nonexpert in fetal brain examiner. Detection of structures in the proximal hemisphere was significantly higher when observed through the proximal hemisphere plane rather than the transventricular plane. CONCLUSION: Our results suggest that inclusion of AC and PC complexes visualization, as well as real-time access to the proximal hemisphere, is feasible and could improve the prenatal detection of fetal cerebral anomalies.
Assuntos
Pontos de Referência Anatômicos/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Ultrassonografia Pré-Natal/métodos , Mama/anormalidades , Estudos de Viabilidade , Feminino , Humanos , Hipertrofia , Gravidez , Estudos ProspectivosRESUMO
Brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of pentameric acetylcholine-gated cation channels, have been suggested as molecular targets for the treatment of alcohol abuse and dependence. Here, we examined the effect of the competitive nAChR antagonist UFR2709 on the alcohol consumption of high-alcohol-drinking UChB rats. UChB rats were given free access to ethanol for 24-h periods in a two-bottle free choice paradigm and their ethanol and water intake were measured. The animals were i.p. injected daily for 17 days with a 10, 5, 2.5, or 1 mg/kg dose of UFR2709. Potential confounding motor effects of UFR2709 were assessed by examining the locomotor activity of animals administered the highest dose of UR2709 tested (10 mg/kg i.p.). UFR2709 reduced ethanol consumption and ethanol preference and increased water consumption in a dose-dependent manner. The most effective dose of UFR2709 was 2.5 mg/kg, which induced a 56% reduction in alcohol consumption. Administration of UFR2709 did not affect the weight or locomotor activity of the rats, suggesting that its effects on alcohol consumption and preference were mediated by specific nAChRs.
RESUMO
Alcohol abuse is a worldwide health problem with high economic costs to health systems. Emerging evidence suggests that modulation of brain nicotinic acetylcholine receptors (nAChRs) may be a therapeutic target for alcohol dependence. In this work, we assess the effectiveness of four doses of erysodine (1.5, 2.0, 4.0 or 8.0â¯mg/kg/day, i.p.), a competitive antagonist of nAChRs, on voluntary ethanol consumption behavior in alcohol-preferring UChB rats, administered during three consecutive days. Results show that erysodine administration produces a dose-dependent reduction in ethanol consumption respect to saline injection (control group). The highest doses of erysodine (4 and 8â¯mg/kg) reduce (45 and 66%, respectively) the ethanol intake during treatment period and first day of post-treatment compared to control group. While, the lowest doses of erysodine (1.5 and 2â¯mg/kg) only reduce ethanol intake during one day of treatment period. These effective reductions in ethanol intake were 23 and 29% for 1.5 and 2â¯mg/kg erysodine, respectively. Locomotor activity induced by a high dose of erysodine (10â¯mg/kg) was similar to those observed with saline injection in control rats, showing that the reduction in ethanol intake was not produced by hypolocomotor effect induced by erysodine. This is the first report showing that erysodine reduces ethanol intake in UChB rats in a dose-dependent manner. Our results highlight the role of nAChRs in the reward effects of ethanol and its modulation as a potentially effective pharmacological alternative for alcohol dependence treatment.
Assuntos
Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Di-Hidro-beta-Eritroidina/análogos & derivados , Antagonistas Nicotínicos/farmacologia , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Di-Hidro-beta-Eritroidina/farmacologia , Relação Dose-Resposta a Droga , Etanol/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Ratos Wistar , Receptores Nicotínicos/metabolismo , RecompensaRESUMO
With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole-benzoxazinones (Family I) and benzoxazine-arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with Ki values of 20.3 ± 0.9 µM and 20.2 ± 0.9 µM, respectively. Kinetic inhibition assays showed non-competitive inhibition of AChE by the tested compounds. According to our docking studies, the most active compounds from both series (Families I and II) showed a binding mode similar to donepezil and interact with the same residues.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Benzoxazinas/farmacologia , Inibidores da Colinesterase/farmacologia , Piperazinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Benzoxazinas/síntese química , Benzoxazinas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Donepezila , Desenho de Fármacos , Humanos , Indanos/farmacologia , Simulação de Acoplamento Molecular , Piperazinas/síntese química , Piperazinas/química , Piperidinas/farmacologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: To describe a technique for the visualization and measurement of cerebral aqueduct diameter through a 2D sagittal median plane, and to report its aspect and measurement in fetuses with aqueductal stenosis (AS). METHODS: This was a cross-sectional study of 207 morphologically normal fetuses in low-risk pregnancies between 20 and 36 weeks of gestation. The cerebral aqueduct was visualized transvaginally in a midsagittal plane, and measurements of its greatest diameter (ampulla) were taken independently by an expert and a nonexpert sonographer. In addition, the aqueduct morphology from 7 fetuses with AS and complete follow-up were compared to the reference range. RESULTS: Aqueductal measurements were obtained in 206 of 207 normal fetuses. Aqueductal growth occurred linearly with gestational age. Our method demonstrated excellent interobserver reproducibility. Among the 7 fetuses with AS, the aqueductal lumen could not be identified in 6 and had a funneling aspect in 1. DISCUSSION: Our study demonstrated that it is possible to visualize and measure the cerebral aqueduct directly through a 2D ultrasound median plane. In fetuses with severe ventriculomegaly, the morphology and width of this structure could represent a relevant tool in improving AS diagnosis, differentiating it from other causes of significant ventricular dilation that carry a different outcome.
Assuntos
Aqueduto do Mesencéfalo/diagnóstico por imagem , Hidrocefalia/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Gravidez , Ultrassonografia Pré-NatalRESUMO
A series of novel 3-indolylpropyl derivatives was synthesized and evaluated for their binding affinities at the serotonin-1A receptor subtype (5-HT1A R) and the 5-HT transporter (SERT). Compounds 11b and 14b exhibited the highest affinities at the 5-HT1A R (Ki = 43 and 56 nM), whereas compounds 11c and 14a were the most potent analogs at the SERT (Ki = 34 and 17 nM). On the other hand, compounds 14b and 11d showed potent activity at both targets, displaying a profile that makes them promising leads for the search for novel potent ligands with a dual mechanism of action. Molecular docking studies in all the compounds unveiled relevant drug-target interactions, which allowed rationalizing the observed affinities.