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1.
Int J Mol Sci ; 23(22)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36430321

RESUMO

Methylmercury (MeHg) is highly toxic to the human brain. Although much is known about MeHg neurotoxic effects, less is known about how chronic MeHg affects hippocampal amino acids and other neurochemical markers in adult mice. In this study, we evaluated the MeHg effects on systemic lipids and inflammation, hippocampal oxidative stress, amino acid levels, neuroinflammation, and behavior in adult male mice. Challenged mice received MeHg in drinking water (2 mg/L) for 30 days. We assessed weight gain, total plasma cholesterol (TC), triglycerides (TG), endotoxin, and TNF levels. Hippocampal myeloperoxidase (MPO), malondialdehyde (MDA), acetylcholinesterase (AChE), amino acid levels, and cytokine transcripts were evaluated. Mice underwent open field, object recognition, Y, and Barnes maze tests. MeHg-intoxicated mice had higher weight gain and increased the TG and TC plasma levels. Elevated circulating TNF and LPS confirmed systemic inflammation. Higher levels of MPO and MDA and a reduction in IL-4 transcripts were found in the hippocampus. MeHg-intoxication led to increased GABA and glycine, reduced hippocampal taurine levels, delayed acquisition in the Barnes maze, and poor locomotor activity. No significant changes were found in AChE activity and object recognition. Altogether, our findings highlight chronic MeHg-induced effects that may have long-term mental health consequences in prolonged exposed human populations.


Assuntos
Compostos de Metilmercúrio , Animais , Humanos , Masculino , Camundongos , Acetilcolinesterase/metabolismo , Aminoácidos , Hipocampo/metabolismo , Inflamação/induzido quimicamente , Compostos de Metilmercúrio/toxicidade , Compostos de Metilmercúrio/metabolismo , Aumento de Peso , Camundongos Endogâmicos C57BL
2.
BMC Public Health ; 21(1): 1628, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488709

RESUMO

BACKGROUND: Non-communicable diseases are a leading cause of health loss worldwide, in part due to unhealthy lifestyles. Metabolic-based diseases are rising with an unhealthy body-mass index (BMI) in rural areas as the main risk factor in adults, which may be amplified by wider determinants of health. Changes in rural environments reflect the need of better understanding the factors affecting the self-ability for making balanced decisions. We assessed whether unhealthy lifestyles and environment in rural neighbourhoods are reflected into metabolic risks and health capability. METHODS: We conducted a community-based cross-sectional study in 15 Portuguese rural neighbourhoods to describe individuals' health functioning condition and to characterize the community environment. We followed a qualitatively driven mixed-method design to gather information about evidence-based data, lifestyles and neighbourhood satisfaction (incorporated in eVida technology), within a random sample of 270 individuals, and in-depth interviews to 107 individuals, to uncover whether environment influence the ability for improving or pursuing heath and well-being. RESULTS: Men showed to have a 75% higher probability of being overweight than women (p-value = 0.0954); and the reporting of health loss risks was higher in women (RR: 1.48; p-value = 0.122), individuals with larger waist circumference (RR: 2.21; IC: 1.19; 4.27), overweight and obesity (RR: 1.38; p-value = 0.293) and aged over 75 years (RR: 1.78; p-value = 0.235; when compared with participants under 40 years old). Metabolic risks were more associated to BMI and physical activity than diet (or sleeping habits). Overall, metabolic risk linked to BMI was higher in small villages than in municipalities. Seven dimensions, economic development, built (and natural) environment, social network, health care, demography, active lifestyles, and mobility, reflected the self-perceptions in place affecting the individual ability to make healthy choices. Qualitative data exposed asymmetries in surrounding environments among neighbourhoods and uncovered the natural environment and natural resources specifies as the main value of rural well-being. CONCLUSIONS: Metabolic risk factors reflect unhealthy lifestyles and can be associated with environment contextual-dependent circumstances. People-centred approaches highlight wider socioeconomic and (natural) environmental determinants reflecting health needs, health expectations and health capability. Our community-based program and cross-disciplinary research provides insights that may improve health-promoting changes in rural neighbourhoods.


Assuntos
Estilo de Vida , População Rural , Adulto , Idoso , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Masculino , Circunferência da Cintura
3.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803585

RESUMO

Methylmercury (MeHg) toxicity is a major environmental concern. In the aquatic reservoir, MeHg bioaccumulates along the food chain until it is consumed by riverine populations. There has been much interest in the neurotoxicity of MeHg due to recent environmental disasters. Studies have also addressed the implications of long-term MeHg exposure for humans. The central nervous system is particularly susceptible to the deleterious effects of MeHg, as evidenced by clinical symptoms and histopathological changes in poisoned humans. In vitro and in vivo studies have been crucial in deciphering the molecular mechanisms underlying MeHg-induced neurotoxicity. A collection of cellular and molecular alterations including cytokine release, oxidative stress, mitochondrial dysfunction, Ca2+ and glutamate dyshomeostasis, and cell death mechanisms are important consequences of brain cells exposure to MeHg. The purpose of this review is to organize an overview of the mercury cycle and MeHg poisoning events and to summarize data from cellular, animal, and human studies focusing on MeHg effects in neurons and glial cells. This review proposes an up-to-date compendium that will serve as a starting point for further studies and a consultation reference of published studies.


Assuntos
Encéfalo/patologia , Inflamação/patologia , Compostos de Metilmercúrio/toxicidade , Síndromes Neurotóxicas/patologia , Animais , Bioacumulação , Encéfalo/efeitos dos fármacos , Humanos , Compostos de Metilmercúrio/farmacocinética , Microbiota/efeitos dos fármacos , Síndromes Neurotóxicas/microbiologia , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/terapia
4.
J Allergy Clin Immunol ; 144(1): 135-143.e6, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30951790

RESUMO

BACKGROUND: Mobile health can be used to generate innovative insights into optimizing treatment to improve allergic rhinitis (AR) control. OBJECTIVES: A cross-sectional real-world observational study was undertaken in 22 countries to complement a pilot study and provide novel information on medication use, disease control, and work productivity in the everyday life of patients with AR. METHODS: A mobile phone app (Allergy Diary, which is freely available on Google Play and Apple stores) was used to collect the data of daily visual analogue scale (VAS) scores for (1) overall allergic symptoms; (2) nasal, ocular, and asthma symptoms; (3) work; and (4) medication use by using a treatment scroll list including all allergy medications (prescribed and over-the-counter) customized for 22 countries. The 4 most common intranasal medications containing intranasal corticosteroids and 8 oral H1-antihistamines were studied. RESULTS: Nine thousand one hundred twenty-two users filled in 112,054 days of VASs in 2016 and 2017. Assessment of days was informative. Control of days with rhinitis differed between no (best control), single (good control for intranasal corticosteroid-treated days), or multiple (worst control) treatments. Users with the worst control increased the range of treatments being used. The same trend was found for asthma, eye symptoms, and work productivity. Differences between oral H1-antihistamines were found. CONCLUSIONS: This study confirms the usefulness of the Allergy Diary in accessing and assessing behavior in patients with AR. This observational study using a very simple assessment tool (VAS) on a mobile phone had the potential to answer questions previously thought infeasible.


Assuntos
Corticosteroides/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Aplicativos Móveis , Rinite Alérgica/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Eficiência , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Avaliação de Sintomas , Escala Visual Analógica , Adulto Jovem
5.
Int J Mol Sci ; 21(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046230

RESUMO

The European Calcium Society (ECS) workshop, which is held every 2 years, is a dedicated meeting of scientists interested in the elucidation of the action of calcium binding, calcium signaling and the study of proteins and organelles, such as mitochondria and endoplasmic reticulum, thereby involved, either in health and disease conditions. The 8th edition of the ECS workshop was organized by a group of researchers from the University of Coimbra, Portugal, in close collaboration with ECS board members. Thanks to the central role of "Calcium Signaling in Aging and Neurodegenerative Disorders", the ECS 2019 workshop was attended by 62 experts who presented their results in a plenary lecture and five regular symposia, two oral communication sessions and two poster sessions, followed by a hands-on session on calcium imaging. All the scientific and social events were fully participated by the scientific community that allowed a close and fruitful interaction and discussion between junior researchers and senior experts in the field. In this report, the contributions in individual sessions are summarized.


Assuntos
Envelhecimento/metabolismo , Sinalização do Cálcio , Doenças Neurodegenerativas/metabolismo , Animais , Humanos , Sociedades Científicas
6.
Clin Exp Allergy ; 49(4): 442-460, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30597673

RESUMO

BACKGROUND: Mobile technology may help to better understand the adherence to treatment. MASK-rhinitis (Mobile Airways Sentinel NetworK for allergic rhinitis) is a patient-centred ICT system. A mobile phone app (the Allergy Diary) central to MASK is available in 22 countries. OBJECTIVES: To assess the adherence to treatment in allergic rhinitis patients using the Allergy Diary App. METHODS: An observational cross-sectional study was carried out on all users who filled in the Allergy Diary from 1 January 2016 to 1 August 2017. Secondary adherence was assessed by using the modified Medication Possession Ratio (MPR) and the Proportion of days covered (PDC) approach. RESULTS: A total of 12 143 users were registered. A total of 6 949 users reported at least one VAS data recording. Among them, 1 887 users reported ≥7 VAS data. About 1 195 subjects were included in the analysis of adherence. One hundred and thirty-six (11.28%) users were adherent (MPR ≥70% and PDC ≤1.25), 51 (4.23%) were partly adherent (MPR ≥70% and PDC = 1.50) and 176 (14.60%) were switchers. On the other hand, 832 (69.05%) users were non-adherent to medications (MPR <70%). Of those, the largest group was non-adherent to medications and the time interval was increased in 442 (36.68%) users. CONCLUSION AND CLINICAL RELEVANCE: Adherence to treatment is low. The relative efficacy of continuous vs on-demand treatment for allergic rhinitis symptoms is still a matter of debate. This study shows an approach for measuring retrospective adherence based on a mobile app. This also represents a novel approach for analysing medication-taking behaviour in a real-world setting.


Assuntos
Uso do Telefone Celular , Adesão à Medicação , Aplicativos Móveis , Rinite Alérgica/epidemiologia , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Rinite Alérgica/diagnóstico , Rinite Alérgica/terapia , Inquéritos e Questionários
7.
J Neurosci ; 36(37): 9558-71, 2016 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-27629708

RESUMO

UNLABELLED: Although we are beginning to understand the late stage of neurodegenerative diseases, the molecular defects associated with the initiation of impaired cognition are poorly characterized. Here, we demonstrate that in the adult brain, the coxsackievirus and adenovirus receptor (CAR) is located on neuron projections, at the presynapse in mature neurons, and on the soma of immature neurons in the hippocampus. In a proinflammatory or diseased environment, CAR is lost from immature neurons in the hippocampus. Strikingly, in hippocampi of patients at early stages of late-onset Alzheimer's disease (AD), CAR levels are significantly reduced. Similarly, in triple-transgenic AD mice, CAR levels in hippocampi are low and further reduced after systemic inflammation. Genetic deletion of CAR from the mouse brain triggers deficits in adult neurogenesis and synapse homeostasis that lead to impaired hippocampal plasticity and cognitive deficits. We propose that post-translational CAR loss of function contributes to cognitive defects in healthy and diseased-primed brains. SIGNIFICANCE STATEMENT: This study addressed the role of the coxsackievirus and adenovirus receptor (CAR), a single-pass cell adhesion molecule, in the adult brain. Our results demonstrate that CAR is expressed by mature neurons throughout the brain. In addition, we propose divergent roles for CAR in immature neurons, during neurogenesis, and at the mature synapse. Notably, CAR loss of function also affects hippocampal plasticity.


Assuntos
Doença de Alzheimer/patologia , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/deficiência , Hipocampo/patologia , Neurogênese/genética , Plasticidade Neuronal/genética , Sinapses/metabolismo , Fatores Etários , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Animais , Células Cultivadas , Transtornos Cognitivos/etiologia , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Embrião de Mamíferos , Potenciais Pós-Sinápticos Excitadores/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Nestina/genética , Nestina/metabolismo
8.
Purinergic Signal ; 13(4): 467-478, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28707031

RESUMO

Cell signaling mediated by P2X7 receptors (P2X7R) has been suggested to be involved in epileptogenesis, via modulation of intracellular calcium levels, excitotoxicity, activation of inflammatory cascades, and cell death, among other mechanisms. These processes have been described to be involved in pilocarpine-induced status epilepticus (SE) and contribute to hyperexcitability, resulting in spontaneous and recurrent seizures. Here, we aimed to investigate the role of P2X7R in epileptogenesis in vivo using RNA interference (RNAi) to inhibit the expression of this receptor. Small interfering RNA (siRNA) targeting P2X7R mRNA was injected into the lateral ventricles (icv) 6 h after SE. Four groups were studied: Saline-Vehicle, Saline-siRNA, Pilo-Vehicle, and Pilo-siRNA. P2X7R was quantified by western blotting and neuronal death assessed by Fluoro-Jade B histochemistry. The hippocampal volume (edema) was determined 48 h following RNAi. Behavioral parameters as latency to the appearance of spontaneous seizures and the number of seizures were determined until 60 days after the SE onset. The Saline-siRNA and Pilo-siRNA groups showed a 43 and 37% reduction, respectively, in P2X7R protein levels compared to respective vehicle groups. Neuroprotection was observed in CA1 and CA3 of the Pilo-siRNA group compared to Pilo-Vehicle. P2X7R silencing in pilocarpine group reversed the increase in the edema detected in the hilus, suprapyramidal dentate gyrus, CA1, and CA3; reduced mortality rate following SE; increased the time to onset of spontaneous seizure; and reduced the number of seizures, when compared to the Pilo-Vehicle group. Therefore, our data highlights the potential of P2X7R as a therapeutic target for the adjunct treatment of epilepsy.


Assuntos
Epilepsia/metabolismo , Hipocampo/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Animais , Convulsivantes/toxicidade , Epilepsia/induzido quimicamente , Técnicas de Silenciamento de Genes , Masculino , Pilocarpina/toxicidade , Interferência de RNA , Ratos , Ratos Wistar
9.
BMC Neurosci ; 15: 100, 2014 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-25156632

RESUMO

BACKGROUND: Accumulating evidence suggests that growth hormone (GH) may play a major role in the regulation of postnatal neurogenesis, thus supporting the possibility that it may be also involved in promoting brain repair after brain injury. In order to gain further insight on this possibility, in this study we have investigated the pathways signaling the effect of GH treatment on the proliferation and survival of hippocampal subgranular zone (SGZ)-derived neurospheres. RESULTS: Our results demonstrate that GH treatment promotes both proliferation and survival of SGZ neurospheres. By using specific chemical inhibitors we have been also able to demonstrate that GH treatment promotes the activation of both Akt-mTOR and JNK signaling pathways, while blockade of these pathways either reduces or abolishes the GH effects. In contrast, no effect of GH on the activation of the Ras-ERK pathway was observed after GH treatment, despite blockade of this signaling path also resulted in a significant reduction of GH effects. Interestingly, SGZ cells were also capable of producing GH, and blockade of endogenous GH also resulted in a decrease in the proliferation and survival of SGZ neurospheres. CONCLUSIONS: Altogether, our findings suggest that GH treatment may promote the proliferation and survival of neural progenitors. This effect may be elicited by cooperating with locally-produced GH in order to increase the response of neural progenitors to adequate stimuli. On this view, the possibility of using GH treatment to promote neurogenesis and cell survival in some acquired neural injuries may be envisaged.


Assuntos
Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Hormônio do Crescimento/metabolismo , Hipocampo/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hormônio do Crescimento/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Proteínas ras/antagonistas & inibidores , Proteínas ras/metabolismo
10.
Front Immunol ; 15: 1360065, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38558823

RESUMO

Mounting evidence progressively appreciates the vital interplay between immunity and metabolism in a wide array of immunometabolic chronic disorders, both autoimmune and non-autoimmune mediated. The immune system regulates the functioning of cellular metabolism within organs like the brain, pancreas and/or adipose tissue by sensing and adapting to fluctuations in the microenvironment's nutrients, thereby reshaping metabolic pathways that greatly impact a pro- or anti-inflammatory immunophenotype. While it is agreed that the immune system relies on an adequate nutritional status to function properly, we are only just starting to understand how the supply of single or combined nutrients, all of them termed immunonutrients, can steer immune cells towards a less inflamed, tolerogenic immunophenotype. Polyphenols, a class of secondary metabolites abundant in Mediterranean foods, are pharmacologically active natural products with outstanding immunomodulatory actions. Upon binding to a range of receptors highly expressed in immune cells (e.g. AhR, RAR, RLR), they act in immunometabolic pathways through a mitochondria-centered multi-modal approach. First, polyphenols activate nutrient sensing via stress-response pathways, essential for immune responses. Second, they regulate mammalian target of rapamycin (mTOR)/AMP-activated protein kinase (AMPK) balance in immune cells and are well-tolerated caloric restriction mimetics. Third, polyphenols interfere with the assembly of NLR family pyrin domain containing 3 (NLRP3) in endoplasmic reticulum-mitochondria contact sites, inhibiting its activation while improving mitochondrial biogenesis and autophagosome-lysosome fusion. Finally, polyphenols impact chromatin remodeling and coordinates both epigenetic and metabolic reprogramming. This work moves beyond the well-documented antioxidant properties of polyphenols, offering new insights into the multifaceted nature of these compounds. It proposes a mechanistical appraisal on the regulatory pathways through which polyphenols modulate the immune response, thereby alleviating chronic low-grade inflammation. Furthermore, it draws parallels between pharmacological interventions and polyphenol-based immunonutrition in their modes of immunomodulation across a wide spectrum of socioeconomically impactful immunometabolic diseases such as Multiple Sclerosis, Diabetes (type 1 and 2) or even Alzheimer's disease. Lastly, it discusses the existing challenges that thwart the translation of polyphenols-based immunonutritional interventions into long-term clinical studies. Overcoming these limitations will undoubtedly pave the way for improving precision nutrition protocols and provide personalized guidance on tailored polyphenol-based immunonutrition plans.


Assuntos
Mitocôndrias , Polifenóis , Humanos , Polifenóis/farmacologia , Mitocôndrias/metabolismo , Sistema Imunitário/metabolismo , Inflamação/metabolismo , Tecido Adiposo/metabolismo
11.
Stem Cells ; 30(4): 773-84, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22893458

RESUMO

Neural stem/progenitor cells present in the subventricular zone (SVZ) are a potential source of repairing cells after injury. Therefore, the identification of novel players that modulate neural stem cells differentiation can have a huge impact in stem cell-based therapies. Herein, we describe a unique role of histamine in inducing functional neuronal differentiation from cultured mouse SVZ stem/progenitor cells. This proneurogenic effect depends on histamine 1 receptor activation and involves epigenetic modifications and increased expression of Mash1, Dlx2, and Ngn1 genes. Biocompatible poly (lactic-co-glycolic acid) microparticles, engineered to release histamine in a controlled and prolonged manner, also triggered robust neuronal differentiation in vitro. Preconditioning with histamine-loaded microparticles facilitated neuronal differentiation of SVZ-GFP cells grafted in hippocampal slices and in in vivo rodent brain. We propose that neuronal commitment triggered by histamine per se or released from biomaterial-derived vehicles may represent a new tool for brain repair strategies.


Assuntos
Histamina/farmacologia , Animais , Técnicas de Cultura de Células , Diferenciação Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Histamina/administração & dosagem , Histamina/química , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Ventrículos Laterais/citologia , Ventrículos Laterais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
13.
Pharmaceutics ; 15(4)2023 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-37111572

RESUMO

Apolipoprotein E (apoE) mimetic peptides are engineered fragments of the native apoE protein's LDL-receptor binding site that improve the outcomes following a brain injury and intestinal inflammation in a variety of models. The vicious cycle of enteric infections and malnutrition is closely related to environmental-driven enteric dysfunction early in life, and such chronic inflammatory conditions may blunt the developmental trajectories of children with worrisome and often irreversible physical and cognitive faltering. This window of time for microbiota maturation and brain plasticity is key to protecting cognitive domains, brain health, and achieving optimal/full developmental potential. This review summarizes the potential role of promising apoE mimetic peptides to improve the function of the gut-brain axis, including targeting the blood-brain barrier in children afflicted with malnutrition and enteric infections.

14.
J Neurochem ; 123(6): 1041-53, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23061411

RESUMO

Methamphetamine (METH) is a psychostimulant drug that causes irreversible brain damage leading to several neurological and psychiatric abnormalities, including cognitive deficits. Neuropeptide Y (NPY) is abundant in the mammalian central nervous system (CNS) and has several important functions, being involved in learning and memory processing. It has been demonstrated that METH induces significant alteration in mice striatal NPY, Y(1) and Y(2) receptor mRNA levels. However, the impact of this drug on the hippocampal NPY system and its consequences remain unknown. Thus, in this study, we investigated the effect of METH intoxication on mouse hippocampal NPY levels, NPY receptors function, and memory performance. Results show that METH increased NPY, Y(2) and Y(5) receptor mRNA levels, as well as total NPY binding accounted by opposite up- and down-regulation of Y(2) and Y(1) functional binding, respectively. Moreover, METH-induced impairment in memory performance and AKT/mammalian target of rapamycin pathway were both prevented by the Y(2) receptor antagonist, BIIE0246. These findings demonstrate that METH interferes with the hippocampal NPY system, which seems to be associated with memory failure. Overall, we concluded that Y(2) receptors are involved in memory deficits induced by METH intoxication.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Hipocampo/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Metanfetamina/toxicidade , Neuropeptídeo Y/antagonistas & inibidores , Neuropeptídeo Y/metabolismo , Animais , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/genética , Receptores de Neuropeptídeo Y/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo
15.
J Neurochem ; 120(1): 93-105, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22007767

RESUMO

Increasing evidences suggest that neuropeptide Y (NPY) may act as a key modulator of the cross-talk between the brain and the immune system in health and disease. In the present study, we dissected the possible inhibitory role of NPY upon inflammation-associated microglial cell motility. NPY, through activation of Y(1) receptors, was found to inhibit lipopolysaccharide (LPS)-induced microglia (N9 cell line) motility. Moreover, stimulation of microglia with LPS was inhibited by IL-1 receptor antagonist (IL-1ra), suggesting the involvement of endogenous interleukin-1 beta (IL-1ß) in this process. Direct stimulation with IL-1ß promoted downstream p38 mitogen-activated protein kinase mobilization and increased microglia motility. Moreover, consistently, p38 mitogen-activated protein kinase inhibition decreased the extent of actin filament reorganization occurring during plasma membrane ruffling and p38 phosphorylation was inhibited by NPY, involving Y(1) receptors. Significantly, the key inhibitory role of NPY on LPS-induced motility of CD11b-positive cells was further confirmed in mouse brain cortex explants. In summary, we revealed a novel functional role for NPY in the regulation of microglial function that may have important implications in the modulation of CNS injuries/diseases where microglia migration/motility might play a role.


Assuntos
Movimento Celular/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/farmacologia , Microglia/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Animais , Western Blotting , Antígeno CD11b/metabolismo , Linhagem Celular , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/ultraestrutura , Interpretação Estatística de Dados , Imuno-Histoquímica , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Neuropeptídeo Y/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
16.
Eur J Neurosci ; 36(9): 3173-83, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22805317

RESUMO

It has been reported that the hippocampus is very susceptible to methamphetamine (METH) and that neuropeptide Y (NPY) is an important neuroprotective agent against hippocampal excitotoxicity. However, there is very little information regarding the role of the NPYergic system in this brain region under conditions of METH toxicity. To clarify this issue, we investigated the role of NPY and its receptors against METH-induced neuronal cell death in hippocampal organotypic slice cultures. Our data show that NPY (1 µm) is neuroprotective in DG, CA3 and CA1 subregions via Y(2) receptors. Moreover, the selective activation of Y(1) receptors (1 µm [Leu(31) ,Pro(34) ]NPY) partially prevented the toxicity induced by METH in DG and CA3 subfields, but completely blocked its toxicity in the CA1 pyramidal cell layer. Regarding Y(2) receptors, its activation (300 nm NPY13-36) completely prevented METH-induced toxicity in all subregions analysed, which involved changes in levels of pro- and anti-apoptotic proteins Bcl-2 and Bax, respectively. Besides neuronal cell death, we also showed that METH triggers a microglial response in the mouse hippocampus which was attenuated by Y(2) receptor activation. To better clarify the effect of METH and the NPY system on microglial cells, we further used the N9 microglial cell line. We found that both NPY and the Y(2) receptor agonist were able to protect microglia against METH-induced cell death. Overall, our data demonstrate that METH is toxic to both neurons and microglial cells, and that NPY, mainly via Y(2) receptors, has an important protective role against METH-induced cell death and microgliosis.


Assuntos
Hipocampo/efeitos dos fármacos , Metanfetamina/toxicidade , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Neuropeptídeo Y/genética , Transcrição Gênica , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
17.
Eur J Neurosci ; 35(11): 1672-83, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22506985

RESUMO

Ampakines are chemical compounds known to modulate the properties of ionotropic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-subtype glutamate receptors. The functional effects attributed to ampakines involve plasticity and the increase in synaptic efficiency of neuronal circuits, a process that may be intimately associated with differentiation of newborn neurons. The subventricular zone (SVZ) is the main neurogenic niche of the brain, containing neural stem cells with brain repair potential. Accordingly, the identification of new pharmaceutical compounds with neurogenesis-enhancing properties is important as a tool to promote neuronal replacement based on the use of SVZ cells. The purpose of the present paper is to examine the possible proneurogenic effects of ampakine CX546 in cell cultures derived from the SVZ of early postnatal mice. We observed that CX546 (50 µm) treatment triggered an increase in proliferation, evaluated by BrdU incorporation assay, in the neuroblast lineage. Moreover, by using a cell viability assay (TUNEL) we found that, in contrast to AMPA, CX546 did not cause cell death. Also, both AMPA and CX546 stimulated neuronal differentiation as evaluated morphologically through neuronal nuclear protein (NeuN) immunocytochemistry and functionally by single-cell calcium imaging. Accordingly, short exposure to CX546 increased axonogenesis, as determined by the number and length of tau-positive axons co-labelled for the phosphorylated form of SAPK/JNK (P-JNK), and dendritogenesis (MAP2-positive neurites). Altogether, this study shows that ampakine CX546 promotes neurogenesis in SVZ cell cultures and thereby may have potential for future stem cell-based therapies.


Assuntos
Proliferação de Células/efeitos dos fármacos , Dioxóis/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Piperidinas/farmacologia , Telencéfalo/citologia , Telencéfalo/embriologia , Animais , Animais Recém-Nascidos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Cultura Primária de Células
18.
J Neurosci ; 30(13): 4573-84, 2010 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-20357108

RESUMO

In the adult mammalian brain, the subventricular zone (SVZ) hosts stem cells constantly generating new neurons. Angiopoietin-1 (Ang-1) is an endothelial growth factor with a critical role in division, survival, and adhesion of endothelial cells via Tie-2 receptor activity. Expression of Tie-2 in nonendothelial cells, especially neurons and stem cells, suggests that Ang-1 may be involved in neurogenesis. In the present work, we investigated the putative role of Ang-1 on SVZ neurogenesis. Immature cells from SVZ-derived neurospheres express Ang-1 and Tie-2 mRNA, suggesting a role for the Ang-1/Tie-2 system in the neurogenic niche. Moreover, we also found that Tie-2 protein expression is retained on differentiation in neurons and glial cells. Ang-1 triggered proliferation via activation of the ERK1/2 (extracellular signal-regulated kinase 1/2) mitogen-activated protein kinase (MAPK) kinase pathway but did not induce cell death. Accordingly, coincubation with an anti-Tie-2 neutralizing antibody prevented the pro-proliferative effect of Ang-1. Furthermore, Ang-1 increased the number of NeuN (neuronal nuclear protein)-positive neurons in cultures treated for 7 d, as well as the number of functional neurons, as assessed by monitoring [Ca(2+)](i) rises after application of specific stimuli for neurons and immature cells. The proneurogenic effect of Ang-1 is mediated by Tie-2 activation and subsequent mTOR (mammalian target of rapamycin kinase) mobilization. In agreement, neuronal differentiation significantly decreased after exposure to an anti-Tie-2 neutralizing antibody and to rapamycin. Moreover, Ang-1 elicited the activation of the SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase) MAPK, involved in axonogenesis. Our work shows a proneurogenic effect of Ang-1, highlighting the relevance of blood vessel/stem cell cross talk in health and disease.


Assuntos
Angiopoietina-1/fisiologia , Encéfalo/citologia , Neurônios/fisiologia , Células-Tronco/fisiologia , Angiopoietina-1/biossíntese , Angiopoietina-1/genética , Animais , Axônios/fisiologia , Encéfalo/crescimento & desenvolvimento , Morte Celular , Diferenciação Celular , Proliferação de Células , Ventrículos Cerebrais/citologia , Ventrículos Cerebrais/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese , Neuroglia/citologia , Neuroglia/fisiologia , Neurônios/citologia , Bulbo Olfatório/citologia , Bulbo Olfatório/crescimento & desenvolvimento , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/biossíntese , Receptor TIE-2/biossíntese , Receptor TIE-2/genética , Células-Tronco/citologia , Serina-Treonina Quinases TOR
19.
J Biol Chem ; 285(53): 41921-34, 2010 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-20959451

RESUMO

Given the modulatory role of neuropeptide Y (NPY) in the immune system, we investigated the effect of NPY on the production of NO and IL-1ß in microglia. Upon LPS stimulation, NPY treatment inhibited NO production as well as the expression of inducible nitric-oxide synthase (iNOS). Pharmacological studies with a selective Y(1) receptor agonist and selective antagonists for Y(1), Y(2), and Y(5) receptors demonstrated that inhibition of NO production and iNOS expression was mediated exclusively through Y(1) receptor activation. Microglial cells stimulated with LPS and ATP responded with a massive release of IL-1ß, as measured by ELISA. NPY inhibited this effect, suggesting that it can strongly impair the release of IL-1ß. Furthermore, we observed that IL-1ß stimulation induced NO production and that the use of a selective IL-1 receptor antagonist prevented NO production upon LPS stimulation. Moreover, NPY acting through Y(1) receptor inhibited LPS-stimulated release of IL-1ß, inhibiting NO synthesis. IL-1ß activation of NF-κB was inhibited by NPY treatment, as observed by confocal microscopy and Western blotting analysis of nuclear translocation of NF-κB p65 subunit, leading to the decrease of NO synthesis. Our results showed that upon LPS challenge, microglial cells release IL-1ß, promoting the production of NO through a NF-κB-dependent pathway. Also, NPY was able to strongly inhibit NO synthesis through Y(1) receptor activation, which prevents IL-1ß release and thus inhibits nuclear translocation of NF-κB. The role of NPY in key inflammatory events may contribute to unravel novel gateways to modulate inflammation associated with brain pathology.


Assuntos
Interleucina-1beta/metabolismo , Microglia/metabolismo , Neuropeptídeo Y/química , Óxido Nítrico/química , Receptores de Neuropeptídeo Y/metabolismo , Transporte Ativo do Núcleo Celular , Trifosfato de Adenosina/química , Animais , Núcleo Celular/metabolismo , Citosol/metabolismo , Ensaio de Imunoadsorção Enzimática/métodos , Inflamação , Lipopolissacarídeos/química , Camundongos , NF-kappa B/metabolismo
20.
J Neurochem ; 116(6): 1018-27, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21175616

RESUMO

The subventricular zone (SVZ) is a major reservoir for stem cells in the adult mammalian brain. Neural stem cells supply the olfactory bulb with new interneurons and provide cells that migrate towards lesioned brain areas. Neuropeptide Y (NPY), one of the most abundant neuropeptides in the brain, was previously shown to induce neuroproliferation on mice SVZ cells. In the present study, performed in rats, we demonstrate the endogenous synthesis of NPY by cells in the SVZ that suggests that NPY could act as an autocrine/paracrine factor within the SVZ area. We observed that NPY promotes SVZ cell proliferation as previously reported in mice, but does not affect self-renewal of SVZ stem cells. Additionally, this study provides the first direct evidence of a chemokinetic activity of NPY on SVZ cells. Using pharmacological approaches, we demonstrate that both the mitogenic and chemokinetic properties of NPY involve Y1 receptor-mediated activation of the ERK1/2 MAP kinase pathway. Altogether, our data establish that NPY through Y1 receptors activation controls chemokinetic activity and, as for mice, is a major neuroproliferative regulator of rat SVZ cells.


Assuntos
Movimento Celular/fisiologia , Ventrículos Cerebrais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Neurônios/fisiologia , Neuropeptídeo Y/metabolismo , Animais , Animais Recém-Nascidos , Arginina/análogos & derivados , Arginina/farmacologia , Bromodesoxiuridina/metabolismo , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neuropeptídeo Y/análogos & derivados , Neuropeptídeo Y/genética , Neuropeptídeo Y/farmacologia , Fragmentos de Peptídeos/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo
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