Percorrer por autor "Santos, Ana Isabel"
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- Caffeine reverts memory but not mood impairment in a depression-prone mouse strain with up-regulated Adenosine A(2A) receptor in hippocampal glutamate synapsesPublication . Machado, Nuno J.; Simoes, Ana Patricia; Silva, Henrique B.; Ardais, Ana Paula; Kaster, Manuella P.; Garcao, Pedro; Rodrigues, Diana I.; Pochmann, Daniela; Santos, Ana Isabel; Araújo, Inês; Porciuncula, Lisiane O.; Tome, Angelo R.; Kofalvi, Attila; Vaugeois, Jean-Marie; Agostinho, Paula; El Yacoubi, Malika; Cunha, Rodrigo A.; Gomes, Catarina A.Caffeine prophylactically prevents mood and memory impairments through adenosine A(2A) receptor (A(2A)R) antagonism. A(2A)R antagonists also therapeutically revert mood and memory impairments, but it is not known if caffeine is also therapeutically or only prophylactically effective. Since depression is accompanied by mood and memory alterations, we now explored if chronic (4 weeks) caffeine consumption (0.3 g/L) reverts mood and memory impairment in helpless mice (HM, 12 weeks old), a bred-based model of depression. HM displayed higher immobility in the tail suspension and forced swimming tests, greater anxiety in the elevated plus maze, and poorer memory performance (modified Y-maze and object recognition). HM also had reduced density of synaptic (synaptophysin, SNAP-25), namely, glutamatergic (vGluT1; -22 +/- 7 %) and GABAergic (vGAT; -23 +/- 8 %) markers in the hippocampus. HM displayed higher A(2A)R density (72 +/- 6 %) in hippocampal synapses, an enhanced facilitation of hippocampal glutamate release by the A(2A)R agonist, CGS21680 (30 nM), and a larger LTP amplitude (54 +/- 8 % vs. 21 +/- 5 % in controls) that was restored to control levels (30 +/- 10 %) by the A(2A)R antagonist, SCH58261 (50 nM). Notably, caffeine intake reverted memory deficits and reverted the loss of hippocampal synaptic markers but did not affect helpless or anxiety behavior. These results reinforce the validity of HM as an animal model of depression by showing that they also display reference memory deficits. Furthermore, caffeine intake selectively reverted memory but not mood deficits displayed by HM, which are associated with an increased density and functional impact of hippocampal A(2A)R controlling synaptic glutamatergic function.
- Differential contribution of the guanylyl cyclase-cyclic GMP-protein kinase g pathway to the proliferation of neural stem cells stimulated by nitric oxidePublication . Carreira, Bruno P.; Morte, Maria Inêss; Lourenço, Ana Sofia; Santos, Ana Isabel; Inácio, Ângela; Ambrósio, António F.; Carvalho, Caetana M.; Araújo, InêsNitric oxide (NO) is an important inflammatory mediator involved in the initial boost in the proliferation of neural stem cells following brain injury. However, the mechanisms underlying the proliferative effect of NO are still unclear. The aim of this work was to investigate whether cyclic GMP (cGMP) and the cGMP-dependent kinase (PKG) are involved in the proliferative effect triggered by NO in neural stem cells. For this purpose, cultures of neural stem cells isolated from the mouse subventricular zone (SVZ) were used. We observed that long-term exposure to the NO donor (24 h), NOC-18, increased the proliferation of SVZ cells in a cGMP-dependent manner, since the guanylate cyclase inhibitor, ODQ, prevented cell proliferation. Similarly to NOC-18, the cGMP analogue, 8-Br-cGMP, also increased cell proliferation. Interestingly, shorter exposures to NO (6 h) increased cell proliferation in a cGMP-independent manner via the ERK/MAP kinase pathway. The selective inhibitor of PKG, KT5823, prevented the proliferative effect induced by NO at 24 h but not at 6 h. In conclusion, the proliferative effect of NO is initially mediated by the ERK/MAPK pathway, and at later stages by the GC/cGMP/PKG pathway. Thus, our work shows that NO induces neural stem cell proliferation by targeting these two pathways in a biphasic manner. Copyright (C) 2012 S. Karger AG, Basel
- Identification of new targets of S-nitrosylation in neural stem cells by thiol redox proteomicsPublication . Santos, Ana Isabel; Lourenco, Ana S.; Simão, Sónia; Marques-da-Silva, Dorinda; Santos, Daniela F.; Carvalho, Ana Paula Onofre de; Pereira, Ana Catarina; Izquierdo-Álvarez, Alicia; Ramos, Elena; Morato, Esperanza; Marina, Anabel; Martínez-Ruiz, Antonio; Araújo, InêsNitric oxide (NO) is well established as a regulator of neurogenesis. NO increases the proliferation of neural stem cells (NSC), and is essential for hippocampal injury-induced neurogenesis following an excitotoxic lesion. One of the mechanisms underlying non-classical NO cell signaling is protein S-nitrosylation. This post-translational modification consists in the formation of a nitrosothiol group (R-SNO) in cysteine residues, which can promote formation of other oxidative modifications in those cysteine residues. S-nitrosylation can regulate many physiological processes, including neuronal plasticity and neurogenesis. In this work, we aimed to identify S-nitrosylation targets of NO that could participate in neurogenesis. In NSC, we identified a group of proteins oxidatively modified using complementary techniques of thiol redox proteomics. S-nitrosylation of some of these proteins was confirmed and validated in a seizure mouse model of hippocampal injury and in cultured hippocampal stem cells. The identified S-nitrosylated proteins are involved in the ERK/MAPK pathway and may be important targets of NO to enhance the proliferation of NSC.
- New physical and biological evidence of lateral transport affecting dinoflagellate cyst distribution in the benthic nepheloid layer along a land-sea transect off Figueira da Foz (Atlantic Iberian margin)Publication . García-Moreiras, Iria; Hatherly, Melissa; Zonneveld, Karin; Dubert, Jesus; Nolasco, Rita; Santos, Ana Isabel; Oliveira, Anabela; Moita, Teresa; Oliveira, Paulo B.; Magalhães, Jorge M.; Amorim, Anantroduction The production of resting cysts is a key dispersal and survival strategy of many dinoflagellate species. However, little is known about the role of suspended cysts in the benthic nepheloid layer (BNL) in the initiation and decline of planktonic populations.Methods In September 2019, sampling of the dinoflagellate cyst community at different water depths in the water column and in the bottom sediments, and studies of spatio-temporal changes in physical properties (temperature, salinity, density and suspended sediment concentration), were carried out along a land-sea transect off Figueira da Foz (NW Portugal) to investigate the dinoflagellate cyst distribution and the factors (physical and biological) affecting it. A clustering analysis was used to compare the BNL and sediment cyst records with the cyst rain recorded by a sediment trap at a fixed station. Furthermore, Lagrangian particle experiments enabled simulating cyst trajectories in the BNL 5 and 10 days before sampling and assessing cross-shore, vertical and alongshore transport within the studied region.Results A well-developed BNL was present during the survey, which covered a change from active (14th of September) to relaxed (19th of September) upwelling conditions. Organic-walled dinoflagellate cysts were dominant in all samples, although calcareous dinoflagellate cysts consistently occurred (at low abundances). High proportions of full cysts were observed in the BNL, of which a significant portion was viable as shown by excystment experiments. Moreover, BNL cyst records collected on the 19th of September along the land-sea transect were similar to the sediment trap cyst record but greatly differed from sediment cyst records. The heterotrophic small spiny brown cysts (SBC) and cysts of the autotrophic yessotoxin-producer Protoceratium reticulatum notably increased during the survey, in the BNL and in the water column above.Discussion The comparison of the BNL, surface sediment and sediment trap cyst records supported that the main origin of cysts in the BNL was the recent production in the water column. The spatial coincidences in the distribution of cysts and vegetative cells of Protoceratium reticulatum also supported that full cysts in the water column were being produced in surface waters. New data evidenced the presence of a significant reservoir of viable cysts in the BNL that have the potential to seed new planktonic blooms. Furthermore, back-track particle modelling evidenced that alongshore advection was the main physical mechanism controlling cyst dynamics in the BNL during most part of the survey period, being particularly intense in coastal stations (<100 m depth). Consequently, the sediment cyst signal is a mixture of locally and regionally produced cysts. We provide multi-disciplinary data evidencing that cysts recently formed in the photic zone can be laterally advected within the studied region through the BNL, contributing to a better understanding of the role of the BNL in cyst dynamics and tracing the seed sources of the new blooms.
- Nitric Oxide Regulates Neurogenesis in the Hippocampus following SeizuresPublication . Carreira, Bruno P.; Santos, Daniela F.; Santos, Ana Isabel; Carvalho, Caetana M.; Araújo, InêsHippocampal neurogenesis is changed by brain injury. When neuroinflammation accompanies injury, activation of resident microglial cells promotes the release of inflammatory cytokines and reactive oxygen/nitrogen species like nitric oxide (NO). In these conditions, NO promotes proliferation of neural stem cells (NSC) in the hippocampus. However, little is known about the role of NO in the survival and differentiation of newborn cells in the injured dentate gyrus. Here we investigated the role of NO following seizures in the regulation of proliferation, migration, differentiation, and survival of NSC in the hippocampus using the kainic acid (KA) induced seizuremouse model. We show that NO increased the proliferation of NSC and the number of neuroblasts following seizures but was detrimental to the survival of newborn neurons. NO was also required for the maintenance of long-term neuroinflammation. Taken together, our data show that NO positively contributes to the initial stages of neurogenesis following seizures but compromises survival of newborn neurons.
- S-nitrosation and neuronal plasticityPublication . Santos, Ana Isabel; Martinez-Ruiz, A.; Araújo, InêsNitric oxide (NO) has long been recognized as a multifaceted participant in brain physiology. Despite the knowledge that was gathered over many years regarding the contribution of NO to neuronal plasticity, for example the ability of the brain to change in response to new stimuli, only in recent years have we begun to understand how NO acts on the molecular and cellular level to orchestrate such important phenomena as synaptic plasticity (modification of the strength of existing synapses) or the formation of new synapses (synaptogenesis) and new neurons (neurogenesis). Post-translational modification of proteins by NO derivatives or reactive nitrogen species is a non-classical mechanism for signalling by NO. S-nitrosation is a reversible post-translational modification of thiol groups (mainly on cysteines) that may result in a change of function of the modified protein. S-nitrosation of key target proteins has emerged as a main regulatory mechanism by which NO can influence several levels of brain plasticity, which are reviewed in this work. Understanding how S-nitrosation contributes to neural plasticity can help us to better understand the physiology of these processes, and to better address pathological changes in plasticity that are involved in the pathophysiology of several neurological diseases. Linked ArticlesThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit
- Stimulation of neural stem cell proliferation by inhibition of phosphodiesterase 5Publication . Santos, Ana Isabel; Carreira, Bruno P.; Nobre, Rui Jorge; Carvalho, Caetana M.; Araújo, InêsThe involvement of nitric oxide (NO) and cyclic GMP (cGMP) in neurogenesis has been progressively unmasked over the last decade. Phosphodiesterase 5 (PDE5) specifically degrades cGMP and is highly abundant in the mammalian brain. Inhibition of cGMP hydrolysis by blocking PDE5 is a possible strategy to enhance the first step of neurogenesis, proliferation of neural stem cells (NSC). In this work, we have studied the effect on cell proliferation of 3 inhibitors with different selectivity and potency for PDE5, T0156, sildenafil, and zaprinast, using subventricular zone-(SVZ-) derived NSC cultures. We observed that a short-(6 h) or a long-term (24 h) treatment with PDE5 inhibitors increased SVZ-derived NSC proliferation. Cell proliferation induced by PDE5 inhibitors was dependent on the activation of the mitogen-activated protein kinase (MAPK) and was abolished by inhibitors of MAPK signaling, soluble guanylyl cyclase, and protein kinase G. Moreover, sildenafil neither activated ERK1/2 nor altered p27(Kip1) levels, suggesting the involvement of pathways different from those activated by T0156 or zaprinast. In agreement with the present results, PDE5 inhibitors may be an interesting therapeutic approach for enhancing the proliferation stage of adult neurogenesis.