Mood disorders induced by maternal overnutrition : the role of the gut-brain axis on the development of depression and anxiety

Since the first evidence suggesting that maternal nutrition can impact the development of diseases in the offspring, much has been elucidated about its effects on the offspring’s nervous system. Animal studies demonstrated that maternal obesity can predispose the offspring to greater chances of metabolic and neurodevelopmental diseases. However, the mechanisms underlying these responses are not well established. In recent years, the role of the gut-brain axis in the development of anxiety and depression in people with obesity has emerged. Studies investigating changes in the maternal microbiota during pregnancy and also in the offspring demonstrate that conditions such as maternal obesity can modulate the microbiota, leading to long-term outcomes in the offspring. Considering that maternal obesity has also been linked to the development of psychiatric conditions (anxiety and depression), the gut-brain axis is a promising target to be further explored in these neuropsychiatric contexts. In the present study, we review the relationship between maternal obesity and anxious and depressive features, exploring the gut-brain axis as a potential mechanism underlying this relationship

UV SPECTROPHOTOMETRIC METHOD FOR QUANTITATIVE DETERMINATION OF BILASTINE USING EXPERIMENTAL DESIGN FOR ROBUSTNESS

Bilastine is a novel nonsedative H1-receptor antagonist, which may be used for the symptomatic treatment of chronic idiopathic urticaria (CU). This study describes the validation of an UV spectrophotometric method for quantitative determination of bilastine in tablets using 0.1 mol L-1 HCl as solvent. The method was specific, linear, precise, exact and robust at 210 nm, confirming that the method is fast and useful to the routine quality control of bilastine in tablets. The validate method was compared to liquid chromatography (HPLC), which was previously developed and validated to the same drug, and no significative difference between the methods using Student´s t test was found to bilastine quantitation.Bilastine is a novel nonsedative H1-receptor antagonist, which may be used for the symptomatic treatment of chronic idiopathic urticaria (CU). This study describes the validation of an UV spectrophotometric method for quantitative determination of bilastine in tablets using 0.1 mol L-1 HCl as solvent. The method was specific, linear, precise, exact and robust at 210 nm, confirming that the method is fast and useful to the routine quality control of bilastine in tablets. The validate method was compared to liquid chromatography (HPLC), which was previously developed and validated to the same drug, and no significative difference between the methods using Student´s t test was found to bilastine quantitation

Mood Disorders Induced by Maternal Overnutrition: The Role of the Gut-Brain Axis on the Development of Depression and Anxiety

Since the first evidence suggesting that maternal nutrition can impact the development of diseases in the offspring, much has been elucidated about its effects on the offspring’s nervous system. Animal studies demonstrated that maternal obesity can predispose the offspring to greater chances of metabolic and neurodevelopmental diseases. However, the mechanisms underlying these responses are not well established. In recent years, the role of the gut-brain axis in the development of anxiety and depression in people with obesity has emerged. Studies investigating changes in the maternal microbiota during pregnancy and also in the offspring demonstrate that conditions such as maternal obesity can modulate the microbiota, leading to long-term outcomes in the offspring. Considering that maternal obesity has also been linked to the development of psychiatric conditions (anxiety and depression), the gut-brain axis is a promising target to be further explored in these neuropsychiatric contexts. In the present study, we review the relationship between maternal obesity and anxious and depressive features, exploring the gut-brain axis as a potential mechanism underlying this relationship

Lactate Protects Microglia and Neurons from Oxygen-Glucose Deprivation/Reoxygenation

Lactate has received attention as a potential therapeutic intervention for brain diseases, particularly those including energy deficit, exacerbated inflammation, and disrupted redox status, such as cerebral ischemia. However, lactate roles in metabolic or signaling pathways in neural cells remain elusive in the hypoxic and ischemic contexts. Here, we tested the effects of lactate on the survival of a microglial (BV-2) and a neuronal (SH-SY5Y) cell lines during oxygen and glucose deprivation (OGD) or OGD followed by reoxygenation (OGD/R). Lactate signaling was studied by using 3,5-DHBA, an exogenous agonist of lactate receptor GPR81. Inhibition of lactate dehydrogenase (LDH) or monocarboxylate transporters (MCT), using oxamate or 4-CIN, respectively, was performed to evaluate the impact of lactate metabolization and transport on cell viability. The OGD lasted 6 h and the reoxygenation lasted 24 h following OGD (OGD/R). Cell viability, extracellular lactate concentrations, microglial intracellular pH and TNF-ɑ release, and neurite elongation were evaluated. Lactate or 3,5-DHBA treatment during OGD increased microglial survival during reoxygenation. Inhibition of lactate metabolism and transport impaired microglial and neuronal viability. OGD led to intracellular acidification in BV-2 cells, and reoxygenation increased the release of TNF-ɑ, which was reverted by lactate and 3,5-DHBA treatment. Our results suggest that lactate plays a dual role in OGD, acting as a metabolic and a signaling molecule in BV-2 and SH-SY5Y cells. Lactate metabolism and transport are vital for cell survival during OGD. Moreover, lactate treatment and GPR81 activation during OGD promote long-term adaptations that potentially protect cells against secondary cell death during reoxygenation

Administração de lactato como agente neuroprotetor em ratos neonatos submetidos ao modelo de hipóxia-isquemia encefálica

A encefalopatia hipóxico-isquêmica neonatal (EHI) é uma das principais causas de morbidade e mortalidade em recém-nascidos. Atualmente, a hipotermia é a única terapia utilizada para o tratamento da EHI. Entretanto, a hipotermia possui algumas limitações, não sendo eficaz em todos os casos de EHI. Assim, outros possíveis agentes neuroprotetores têm sido testados em modelos animais. O presente trabalho avaliou a utilização de lactato em um modelo animal de hipóxia-isquemia neonatal (HI), que mimetiza em ratos neonatos os danos observados em recém-nascidos humanos. O lactato é um potencial substrato energético do sistema nervoso central (SNC), além de ter demonstrado ação neuroprotetora em modelos de isquemia cerebral em animais adultos. Para a padronização inicial dos experimentos, as concentrações endógenas de lactato foram avaliadas em diferentes momentos após a HI e também após uma injeção intraperitoneal de lactato exógeno. Para investigar o possível papel neuroprotetor do lactato sobre a lesão encefálica e parâmetros comportamentais, ratos Wistar machos e fêmeas com 7 dias de vida foram submetidos à oclusão permanente da artéria carótida comum direita (isquemia) combinada com a exposição a uma atmosfera hipóxica (8% de oxigênio) por 60 minutos (hipóxia). Os animais foram divididos em 4 grupos experimentais: grupo HI (animais submetidos ao procedimento de HI neonatal); grupo HI+LAC (animais submetidos ao procedimento de HI neonatal e que receberam injeções de lactato após a HI); grupo SHAM (animais submetidos a uma cirurgia fictícia e mantidos em normoxia); grupo SHAM+LAC (animais submetidos a uma cirurgia fictícia, mantidos em normoxia e que receberam injeções de lactato). O lactato foi administrado 30 minutos e 2h após a hipóxia (na dose de 2 g/kg) no grupo HI+LAC e nos mesmos momentos no grupo SHAM+LAC. Os grupos HI e SHAM receberam apenas a injeção de veículo (tampão fosfato-salino, PBS). O volume de lesão encefálica foi calculado a partir de fatias coronais dos encéfalos de animais (em P9) coradas com 2,3,5-cloreto de trifeniltetrazólio (TTC), que marca as regiões de células vivas. Os animas foram submetidos aos testes comportamentais de geotaxia negativa e reflexo de endireitamento (em P8 e P14); teste olfatório (em P14); e teste do cilindro (em P20). As concentrações endógenas de lactato retornam aos valores controle 30 minutos após a HI. O lactato exógeno administrado atinge um pico aos 5 minutos (concentração cerca de 4 vezes maior do que a basal) e retorna aos valores basais aos 90 minutos após a injeção. Nos animais submetidos à HI, a administração de lactato reduziu o volume de lesão em P9 e melhorou alguns parâmetros comportamentais em P8 (geotaxia negativa) e em P20 (teste do cilindro), tanto em machos quanto em fêmeas. Assim, parece que o lactato exerce um efeito neuroprotetor de curto prazo, reduzindo a lesão encefálica 48h após a HI (P9), o que parece ter sido importante para a melhora dos desfechos comportamentais observada. Estudos adicionais são necessários para permitir a compreensão dos mecanismos de ação do lactato e sua utilização no tratamento de recém-nascidos que passaram por eventos hipóxicos-isquêmicos encefálicos.Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of mortality and disability in newborns. Currently, the standard approach for treating HIE is therapeutic hypothermia (TH). However, TH shows some limitations, not being efficient in all cases of HIE. Thus, other putative neuroprotective agents have been tested in animal models. The present study evaluated the lactate administration in an animal model of HIE that mimics, in neonatal rats, the brain damage observed in human newborns. Lactate is a potential energy substrate of the central nervous system (CNS), besides its neuroprotective effects have been shown in adult animals following cerebral ischemia. Endogenous concentrations of lactate were evaluated at different time points after HIE and after an intraperitoneal injection of lactate. To investigate the putative neuroprotective role of lactate following brain injury, seven-days-old (P7) male and female Wistar rats underwent permanent common right carotid occlusion (ischemia) combined with an exposition to a hypoxic atmosphere (8% oxygen) for 60 minutes. Animals were assigned to four experimental groups: HI group (animals submitted to HI procedure); HI+LAC group (animals submitted to HI procedure, which received lactate following HI); SHAM group (animals submitted to a fictitious surgery and kept in normoxia); SHAM+LAC group (animals submitted to a fictitious surgery, kept in normoxia and receiving lactate injections). Lactate (2 g/kg) was administered 30 minutes and 2 h after hypoxia in HI+LAC group and at the same times in SHAM+LAC group. HI and SHAM groups received vehicle (phosphate-saline buffer, PBS) injections at the same time points. Volume of brain damage was quantified in coronal brain slices of the animals (P9) stained with 2,3,5-triphenyl tetrazolium chloride (TTC), indicative of viable tissue. Animals underwent behavioral assessments such as negative geotaxis and righting reflex (at P8 and P14), olfactory discrimination (at P14), and cylinder test (P20). Endogenous plasma lactate concentrations return to basal levels 30 minutes after HI. Levels of exogenous lactate reach a peak at 5 minutes and return to basal levels at 90 minutes after injections. In HI animals, lactate administration reduced brain lesion volume in P9 and improved some behavioral parameters in P8 (negative geotaxis) and P20 (cylinder test), for both sexes. Therefore, lactate seems to exert a short-term neuroprotective effect, reducing brain damage 48h following HI (P9), which appear to influence the improvement of behavioral outcomes. Additional studies are necessary in order to understand the mechanisms of action of lactate and its application in the treatment of newborns that underwent hypoxia-ischemia encephalopathy

Evaluation of the functional capacity of the thymus in mice experimentally infected with Plasmodium berghei NK65

Orientador: Liana Maria Cardoso VerinaudDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: O Resumo poderá ser visualizado no texto completo da tese digitalAbstract: The Abstract is available with the full electronic digital documentMestradoImunologiaMestra em Genética e Biologia Molecula