RESUMO
The molecular processes that underlie long-term memory formation involve signaling pathway activation by neurotransmitter release, which induces the expression of immediate early genes, such as Zif268, having a key role in memory formation. In this work, we show that the cannabinoid CB1 receptor signaling is necessary for the effects of dexamethasone on the behavioral response in an inhibitory avoidance task, on dexamethasone-induced ERK phosphorylation, and on dexamethasone-dependent Zif268 expression. Furthermore, we provide primary evidence for the mechanism responsible for this crosstalk between cannabinoid and glucocorticoid-mediated signaling pathways, showing that dexamethasone regulates endocannabinoid metabolism by inhibiting the activity of the Fatty acid amide hydrolase (FAAH), an integral membrane enzyme that hydrolyzes endocannabinoids and related amidated signaling lipids. Our results provide novel evidence regarding the role of the endocannabinoid system, and in particular of the CB1 receptor, as a mediator of the effects of glucocorticoids on the consolidation of aversive memories.
Assuntos
Canabinoides , Consolidação da Memória , Endocanabinoides/metabolismo , Receptor CB1 de Canabinoide/genética , Canabinoides/farmacologia , Transdução de Sinais , Glucocorticoides/farmacologia , Dexametasona/farmacologia , Amidoidrolases , Moduladores de Receptores de Canabinoides/farmacologiaRESUMO
Diabetic retinopathy (DR) is one of the common complications associated with diabetes mellitus and the leading cause of blindness worldwide. Recent research has demonstrated that DR is not only a microvascular disease but may be a result of neurodegenerative processes. Moreover, glucose-induced neuron and glial cell damage may occur shortly after the onset of diabetes which makes the disease hard to diagnose at early stages. SIRT6, a NAD-dependent sirtuin deacylase, modulates aging, energy metabolism, and neurodegeneration. In previous studies we showed that SIRT6 deficiency causes major retinal transmission defects, changes in the expression of glycolytic genes, and elevated levels of apoptosis. Given the importance of glucose availability for retinal function and the critical role of SIRT6 in modulating glycolysis, we aimed to analyze SIRT6 participation in the molecular machinery that regulates the development of experimental DR. Using non-obese diabetic mice, we determined by western blot that 2 weeks after the onset of the disease, high glucose concentrations induced retinal increase in a neovascularization promoting factor (vascular endothelial growth factor, VEGF), and the loss of a neuroprotective factor (brain-derived neurotrophic factor, BDNF) associated with reduced levels of SIRT6 and increased acetylation levels of its substrates (H3K9 and H3K56) suggesting a deregulation of key neural factors. Noteworthy, retinas from CNS conditionally deleted SIRT6 mice showed a resemblance to diabetic retinas exhibiting lower protein levels of BDNF factor and increased protein levels of VEGF. Moreover, cultured Müller glial cells subjected to high glucose concentrations exhibited decreased levels of SIRT6 and increased levels of H3K56 acetylation. In addition, the increment of VEGF levels induced by high glucose was reverted by the over-expression of SIRT6 in this cell type. Accordingly, siRNA experiments showed that, when SIRT6 was silenced, VEGF levels increased. Our findings suggest that epigenetically regulated neurodegenerative events may occur at an early diabetic stage prior to the characteristic proliferative and vascular changes observed at a later diabetic stage.
Assuntos
Retinopatia Diabética/genética , Epigênese Genética , Doenças Neurodegenerativas/genética , Sirtuínas/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Retinopatia Diabética/patologia , Feminino , Inativação Gênica , Glucose/farmacologia , Camundongos , Camundongos Knockout , Neovascularização Patológica/induzido quimicamente , Doenças Neurodegenerativas/patologia , Neuroglia/metabolismo , RNA Interferente Pequeno/farmacologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Preterm birth is a major contributor to early and delayed physical and cognitive impairment. Epidemiological and experimental data indicate that maternal infections are a significant and preventable cause of preterm birth. Recently, melatonin has been suggested to exert neuroprotective effects in several models of brain injury. Here, we sought to investigate whether the administration of melatonin is able to prevent lipopolysaccharide (LPS)-induced fetal brain damage in a model of LPS-induced preterm labor. For this purpose, 15-day pregnant BALB/c mice received intraperitoneally 2 doses of LPS or vehicle: the first one at 10:00 hours (0.26 mg/kg) and the second at 13:00 hours (0.52 mg/kg). On day 14 of pregnancy, a group of mice was subcutaneously implanted with a pellet of 25 mg melatonin. This experimental protocol resulted in 100% of preterm birth and pup death in the LPS group and a 50% of term birth and pup survival in the melatonin + LPS group. In the absence of melatonin, fetuses from LPS-treated mothers showed histological signs of brain damage, microglial/macrophage activation, and higher levels of IL-1ß, inducible nitric oxide synthase (NOS), and neuronal NOS mRNAs as well as increased histone acetyltransferase activity and histone H3 hyperacetylation. In contrast, antenatal administration of melatonin prevented LPS-induced fetal brain damage. Moreover, when behavioral traits were analyzed in the offspring from control, melatonin, and melatonin + LPS, no significant differences were found, suggesting that melatonin prevented LPS-induced long-term neurodevelopmental impairments. Collectively, our results suggest that melatonin could be a new therapeutic tool to prevent fetal brain damage and its long-term consequences induced by maternal inflammation.
Assuntos
Traumatismos do Nascimento/prevenção & controle , Lesões Encefálicas/prevenção & controle , Melatonina/farmacologia , Fármacos Neuroprotetores/farmacologia , Nascimento Prematuro , Animais , Traumatismos do Nascimento/etiologia , Lesões Encefálicas/etiologia , Feminino , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Trabalho de Parto Prematuro/induzido quimicamente , Gravidez , Nascimento Prematuro/induzido quimicamenteRESUMO
Acute stress impairs memory retrieval of several types of memories. An increase in glucocorticoids, several minutes after stressful events, is described as essential to the impairing retrieval-effects of stressors. Moreover, memory retrieval under stress can have long-term consequences. Through what process does the reactivated memory under stress, despite the disrupting retrieval effects, modify long-term memories? The reconsolidation hypothesis proposes that a previously consolidated memory reactivated by a reminder enters a vulnerability phase (labilization) during which it is transiently sensitive to modulation, followed by a re-stabilization phase. However, previous studies show that the expression of memories during reminder sessions is not a condition to trigger the reconsolidation process since unexpressed memories can be reactivated and labilized. Here we evaluate whether it is possible to reactivate-labilize a memory under the impairing-effects of a mild stressor. We used a paradigm of human declarative memory whose reminder structure allows us to differentiate between a reactivated-labile memory state and a reactivated but non-labile state. Subjects memorized a list of five cue-syllables associated with their respective response-syllables. Seventy-two hours later, results showed that the retrieval of the paired-associate memory was impaired when tested 20min after a mild stressor (cold pressor stress (CPS)) administration, coincident with cortisol levels increase. Then, we investigated the long-term effects of CPS administration prior to the reminder session. Under conditions where the reminder initiates the reconsolidation process, CPS impaired the long-term memory expression tested 24h later. In contrast, CPS did not show effects when administered before a reminder session that does not trigger reconsolidation. Results showed that memory reactivation-labilization occurs even when retrieval was impaired. Memory reactivation under stress could hinder -via reconsolidation- the probability of the traces to be expressed in the long term.
Assuntos
Aprendizagem por Associação/fisiologia , Consolidação da Memória/fisiologia , Rememoração Mental/fisiologia , Estresse Fisiológico/fisiologia , Pressão Sanguínea/fisiologia , Temperatura Baixa , Sinais (Psicologia) , Feminino , Humanos , Hidrocortisona/análise , Masculino , Testes Neuropsicológicos , Saliva/químicaRESUMO
Stress is an adaptive response to demands of the environment and thus essential for survival. Exposure to stress during the first years of life has been shown to have profound effects on the growth and development of an adult individual. There are evidences demonstrating that stressful experiences during gestation or in early life can lead to enhanced susceptibility to mental disorders. Early-life stress triggers hypothalamic-pituitary-adrenocortical (HPA) axis activation and the associated neurochemical reactions following glucocorticoid release are accompanied by a rapid physiological response. An excessive response may affect the developing brain resulting in neurobehavioral and neurochemical changes later in life. This article reviews the data from experimental studies aimed to investigate hormonal, functional, molecular and epigenetic mechanisms involved in the stress response during early-life programming. We think these studies might prove useful for the identification of novel pharmacological targets for more effective treatments of mental disorders.
Assuntos
Estresse Psicológico/genética , Animais , Epigênese Genética , Feminino , Humanos , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Gravidez , Efeitos Tardios da Exposição Pré-NatalRESUMO
Pharmacogenetics studies the action of a drug in order to predict the response based on the genetic makeup of an individual. The objective of pharmacogenetic studies is to minimize the adverse effects and to ensure therapeutic benefit. Since psychotropic drugs have a high rate of variability in patient response, the aim of this paper is to update the pharmacogenetic concepts in psychopharmacology in a review that provides tools for rigorous analysis when prescribing a psychotropic drug. The purpose of clinical pharmacogenetic testing is to be able to distinguish between patients who are more or less responders to certain drugs, or on contrary, who are at increased risk for adverse events. The goal is to choose a drug therapy that can maximize the effectiveness in the treatment and minimize the risks of adverse reactions, thus improving the benefit / risk ratio. IN CONCLUSION: technology is not a limiting factor nowadays; the challenge remains, however, to further develop research for clinical use, establishing an appropriate validation test, that is accurate, repeatable and reproducible, in order to safely detect gene sequences of clinical interest.
Assuntos
Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Farmacogenética , Psiquiatria , Sistema Enzimático do Citocromo P-450/genética , HumanosRESUMO
Several studies suggest that negative emotions during pregnancy generate adverse effects on the cognitive, behavioural and emotional development of the descendants. The psychoneuroendocrine pathways involve the transplacentary passage of maternal glucocorticoids in order to influence directly on fetal growth and brain development.Nitric oxide is a gaseous neurotransmitter that plays an important role in the control of neural activity by diffusing into neurons and participates in learning and memory processes. It has been demonstrated that nitric oxide is involved in the regulation of corticosterone secretion. Thus, it has been found that the neuronal isoform of nitric oxide synthase (nNOS) is an endogenous inhibitor of glucocorticoid receptor (GR) in the hippocampus and that nNOS in the hippocampus may participate in the modulation of hypothalamic-pituitary-adrenal axis activity via GR.Neurotrophins are a family of secreted growth factors consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and NT4. Although initially described in the nervous system, they regulate processes such as cell survival, proliferation and differentiation in several other compartments. It has been demonstrated that the NO-citrulline cycle acts together with BDNF in maintaining the progress of neural differentiation.In the present chapter, we explore the interrelation between nitric oxide, glucocorticoids and neurotrophins in brain areas that are key structures in learning and memory processes. The participation of this interrelation in the behavioural and cognitive alterations induced in the offspring by maternal stress is also addressed.
RESUMO
The pathogenesis of atherosclerosis includes the assignment of a critical role to cells of the monocyte/macrophage lineage and to pro-inflammatory cytokines. Niacin is known to improve lipid metabolism and to produce beneficial modification of cardiovascular risk factors. The aim of this work was to investigate if Niacin is able to modulate pro-inflammatory cytokine production in macrophages in a murine model of atherosclerosis. For this purpose C57Bl/6J mice fed with atherogenic diet (AGD) or with conventional chow diet were used. The AGD group showed an increase in body weight and in total plasma cholesterol, with no differences in triglyceride or HDL levels. Lesions in arterial walls were observed. The characterization of Niacin receptor showed an increase in the receptor number of macrophages from the AGD group. Macrophages from control and AGD animals treated in vitro with an inflammatory stimulus showed elevated levels of IL-6, IL-1 and TNF-α, that were even higher in macrophages from AGD mice. Niacin was able to decrease the production of pro-inflammatory cytokines in stimulated macrophages. Similar effect of Niacin was observed in an in vivo model of inflammation. These results show an attenuating inflammatory mechanism for this therapeutic agent and would point out its potential action in plaque stabilization and in the prevention of atherosclerosis progression. Furthermore, the present results provide the basis for future studies on the potential contribution of Niacin to anti-inflammatory therapies.
RESUMO
Prenatal stress (PS) has been linked to abnormal cognitive, behavioral and psychosocial outcomes in both animals and humans. Since PS has been shown to induce a cerebellar cytoarchitectural disarrangement and cerebellar abnormalities that have been linked to an impairment of behavioral functions, the aim of the present work was to investigate whether the exposure to PS in a period in which the cerebellum is still immature can induce behavioral deficits in the adult and whether this alterations are correlated with changes in nitric oxide (NO) and cellular oxidative mechanisms in offspring's cerebellum. Our results show impairments in spatial memory and territory discrimination in PS adult rats. PS offspring also displayed alterations in cerebellar nitric oxide synthase (NOS) expression and activity. Moreover, a correlation between spatial memory deficits and the increase in NOS activity was found. The results found here may point to a role of cerebellar NO in the behavioral alterations induced by stress during early development stages.
Assuntos
Cerebelo/metabolismo , Transtornos da Memória/etiologia , Óxido Nítrico/metabolismo , Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Restrição Física/efeitos adversos , Estresse Psicológico/fisiopatologia , Animais , Comportamento Exploratório/fisiologia , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Óxido Nítrico Sintase Tipo I/biossíntese , Óxido Nítrico Sintase Tipo I/genética , Estresse Oxidativo , Gravidez , Complicações na Gravidez/etiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Distribuição Aleatória , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Estresse Psicológico/etiologiaRESUMO
OBJECTIVE: Periodontitis is an infectious disease leading to inflammation and destruction of tissue surrounding and supporting the tooth. The progress of the inflammatory response depends on the host's immune system and risk factors such as stress. The aim of the present study was to investigate the role of the endocannabinoid anandamide (AEA) in experimental periodontitis with restraint stress, since the endocannabinoid system is known to modulate the hypothalamo-pituitary-adrenal axis as well as immune functions and has been found in human gingival tissues. METHODS: Experimental periodontitis was induced by ligature around first inferior molars and immobilization stress for 2 h twice daily for 7 days in a rat model. RESULTS: Corticosterone plasma levels, locomotor activity, adrenal gland weight and bone loss were increased in periodontitis and stress groups, and there was also less weight gain. The inflammatory parameters such as prostaglandin E(2) (radioimmunoassay), nitric oxide (radioconversion of (14)C-arginine), tumor necrosis factor (TNF)-α (ELISA) and interleukin (IL)-1ß (Western blot) measured in the gingival tissue were significantly increased in the periodontitis groups compared to the control group. Local injection of AEA (10(-8)M, 30 µl) decreased corticosterone plasma levels and the content of the cytokines TNF-α and IL-1ß in gingival tissue in periodontitis-stress groups. These AEA-induced inhibitions were mediated by CB(1) and CB(2) cannabinoid receptors since the injection of both antagonists together, AM251 (10(-6)M) and AM630 (10(-6)M) in 30 µl, prevented these effects. CONCLUSION: The endocannabinoid AEA diminishes the inflammatory response in periodontitis even during a stressful situation.
Assuntos
Anti-Inflamatórios/uso terapêutico , Ácidos Araquidônicos/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Endocanabinoides/uso terapêutico , Periodontite/tratamento farmacológico , Alcamidas Poli-Insaturadas/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/patologia , Animais , Peso Corporal/efeitos dos fármacos , Corticosterona/sangue , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Comportamento Exploratório/efeitos dos fármacos , Indóis/uso terapêutico , Interleucina-1beta/metabolismo , Masculino , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Periodontite/sangue , Periodontite/fisiopatologia , Piperidinas/uso terapêutico , Prostaglandinas E/metabolismo , Pirazóis/uso terapêutico , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Los cambios a largo plazo que se producen en estructura y función del cerebro que acompañan a la exposición crónica a drogas de abuso sugieren que las alteraciones en la regulación de genes contribuyen sustancialmente al fenotipo adictivo. En este capítulo se examinan los múltiples mecanismos por los cuales las drogas alteran el potencial de la transcripción de los genes. Estos mecanismos van desde la movilización o la represión de la maquinaria transcripcional - incluyendo los factores de transcripción DFOSB, el AMP cíclico que responde a las proteínas de elemento de respuesta (CREB) y el factor nuclear-kB (NF-kB) - a la epigenética - incluidas las modificaciones en la accesibilidad de los genes dentro de su estructura de la cromatina nativa inducida por las modificaciones de la cola de histonas y la metilación del ADN, y la regulación de la expresión génica mediante ARN no codificantes. Todas las investigaciones evidencian diversos mecanismos de regulación de genes que inducen las drogas de abuso generando cambios duraderos en el cerebro, y esta revisión describe novedosas propuestas para la terapia de la adicción.(AU)
Long-term changes which result from the chronic exposure to substances of abuse suggest that the alterations in the regulation of genes contribute substantially to the pro-addictive phenotype. These drugs after multiple mechanisms, which include the motility or repression of the transcriptional machinery, as well as epigenetics, and non-coding RNAs regions. All the research evidences different gene regulatory mechanisms induce by substances of abuse, which generate sustainable changes in the brain.(AU)
Assuntos
Humanos , Transtornos Relacionados ao Uso de Substâncias/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/terapia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacosRESUMO
Los cambios a largo plazo que se producen en estructura y función del cerebro que acompañan a la exposición crónica a drogas de abuso sugieren que las alteraciones en la regulación de genes contribuyen sustancialmente al fenotipo adictivo. En este capítulo se examinan los múltiples mecanismos por los cuales las drogas alteran el potencial de la transcripción de los genes. Estos mecanismos van desde la movilización o la represión de la maquinaria transcripcional - incluyendo los factores de transcripción DFOSB, el AMP cíclico que responde a las proteínas de elemento de respuesta (CREB) y el factor nuclear-kB (NF-kB) - a la epigenética - incluidas las modificaciones en la accesibilidad de los genes dentro de su estructura de la cromatina nativa inducida por las modificaciones de la cola de histonas y la metilación del ADN, y la regulación de la expresión génica mediante ARN no codificantes. Todas las investigaciones evidencian diversos mecanismos de regulación de genes que inducen las drogas de abuso generando cambios duraderos en el cerebro, y esta revisión describe novedosas propuestas para la terapia de la adicción.(AU)
Long-term changes which result from the chronic exposure to substances of abuse suggest that the alterations in the regulation of genes contribute substantially to the pro-addictive phenotype. These drugs after multiple mechanisms, which include the motility or repression of the transcriptional machinery, as well as epigenetics, and non-coding RNAs regions. All the research evidences different gene regulatory mechanisms induce by substances of abuse, which generate sustainable changes in the brain.(AU)
Assuntos
Humanos , Transtornos Relacionados ao Uso de Substâncias/patologia , Regulação da Expressão Gênica , Transtornos Relacionados ao Uso de Substâncias/terapia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Ativação TranscricionalRESUMO
Los cambios a largo plazo que se producen en estructura y función del cerebro que acompañan a la exposición crónica a drogas de abuso sugieren que las alteraciones en la regulación de genes contribuyen sustancialmente al fenotipo adictivo. En este capítulo se examinan los múltiples mecanismos por los cuales las drogas alteran el potencial de la transcripción de los genes. Estos mecanismos van desde la movilización o la represión de la maquinaria transcripcional - incluyendo los factores de transcripción DFOSB, el AMP cíclico que responde a las proteínas de elemento de respuesta (CREB) y el factor nuclear-kB (NF-kB) - a la epigenética - incluidas las modificaciones en la accesibilidad de los genes dentro de su estructura de la cromatina nativa inducida por las modificaciones de la cola de histonas y la metilación del ADN, y la regulación de la expresión génica mediante ARN no codificantes. Todas las investigaciones evidencian diversos mecanismos de regulación de genes que inducen las drogas de abuso generando cambios duraderos en el cerebro, y esta revisión describe novedosas propuestas para la terapia de la adicción.
Long-term changes which result from the chronic exposure to substances of abuse suggest that the alterations in the regulation of genes contribute substantially to the pro-addictive phenotype. These drugs after multiple mechanisms, which include the motility or repression of the transcriptional machinery, as well as epigenetics, and non-coding RNAs regions. All the research evidences different gene regulatory mechanisms induce by substances of abuse, which generate sustainable changes in the brain.
Assuntos
Humanos , Ativação Transcricional , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Regulação da Expressão Gênica , Transtornos Relacionados ao Uso de Substâncias/patologia , Transtornos Relacionados ao Uso de Substâncias/terapiaRESUMO
OBJECTIVE: The aim of this study was to assess the short term effect of ethanol administration on periodontal disease in rats. DESIGN: Rats received either ethanol 2g/kg or water by gastric gavage twice a day. On the fifth day ligatures were tied around the molars of half of the rats to induce periodontitis. After 7days gingival tissue was removed and assayed for inflammatory markers. Finally, hemi-mandibles were extracted to evaluate bone loss by histomorphometrical techniques. RESULTS: The experimental periodontitis increased significantly the mRNA expression (p<0.001) and activity (p<0.001) of inducible nitric oxide synthase (iNOS) in the gingival tissue, whilst short time ethanol administration increased iNOS activity (p<0.05) and produced an additive effect on iNOS mRNA expression augmented by periodontitis (p<0.01). The short time ethanol administration also potentiated the periodontitis stimulatory effect on the mRNA expression of interleukin (IL)-1ß (p<0.01 and p<0.001, in semi-quantitative and real time PCR, respectively) and on the height of periodontal ligament (p<0.05). However, the ligature-induced periodontitis, but not ethanol administration, increased the prostaglandin E(2) content (p<0.05) and, diminished the alveolar bone volume (p<0.05), as compared to sham rats. CONCLUSION: The present results suggest that ethanol consumption could represent a risk indicator for periodontal disease since augments the expression of inflammatory markers, in healthy rats, and increases them, at short term, during the illness. However, scale longitudinal investigation and more case-control studies are needed to confirm this statement.
Assuntos
Bebidas Alcoólicas/efeitos adversos , Etanol/efeitos adversos , Mediadores da Inflamação/análise , Periodontite/patologia , Perda do Osso Alveolar/patologia , Processo Alveolar/patologia , Animais , Anti-Inflamatórios/sangue , Biomarcadores/análise , Cromatografia Líquida de Alta Pressão , Corticosterona/sangue , Dinoprostona/análise , Gengiva/química , Gengiva/enzimologia , Interleucina-1beta/análise , Masculino , Óxido Nítrico Sintase Tipo II/análise , Ligamento Periodontal/patologia , Periodontite/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de RiscoRESUMO
Long-term exposure to stressful situations has deleterious effects on adult neurogenesis, behavior, and the immune system. We have previously shown that stressed BALB/c mice show poor learning performance, which correlates with an increase in the T helper 1/T helper 2 (Th1/Th2) cytokine balance. Glatiramer acetate (GA) can stimulate autoreactive T cells. In this work we investigated the effects of GA treatment on BALB/c mice exposed to chronic mild stress (CMS). Stressed mice exhibited a significant decline in their performance in the open field and Y-maze tasks, which was accompanied by a reduction in dentate gyrus neurogenesis and an altered Th1/Th2 balance. Interestingly, after 6 weeks of CMS exposure administration of GA reestablished normal levels of adult neurogenesis, restored the Th1/Th2 balance, and improved learning performance. These results demonstrate that GA treatment can reverse the learning impairment induced by stress through a mechanism that likely involves the regulation of the cytokine balance and adult neurogenesis.
Assuntos
Adjuvantes Imunológicos/farmacologia , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Peptídeos/farmacologia , Estresse Psicológico/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Feminino , Acetato de Glatiramer , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Ionizing radiations can induce oxidative stress on target tissues, acting mainly through reactive oxygen species (ROS). The aim of this work was to investigate if 17-ß-estradiol (ßE) was able to prevent hippocampal-related behavioral and biochemical changes induced by neonatal ionizing radiation exposure and to elucidate a potential neuroprotective mechanism. Male Wistar rats were irradiated with 5 Gy of X-rays between 24 and 48 h after birth. A subset of rats was subcutaneously administered with successive injections of ßE or 17-α-estradiol (αE), prior and after irradiation. Rats were subjected to different behavioral tasks to evaluate habituation and associative memory as well as anxiety levels. Hippocampal ROS levels and protein kinase C (PKC) activity were also assessed. Results show that although ßE was unable to prevent radiation-induced hippocampal PKC activity changes, most behavioral abnormalities were reversed. Moreover, hippocampal ROS levels in ßE-treated irradiated rats approached control values. In addition, αE administered to irradiated animals was effective in preventing radiation-induced alterations. In conclusion, ßE was able to counteract behavioral and biochemical changes induced in irradiated animals, probably acting through an antioxidant mechanism.
Assuntos
Animais Recém-Nascidos , Estradiol/farmacologia , Fármacos Neuroprotetores , Protetores contra Radiação , Animais , Antioxidantes/metabolismo , Ansiedade/psicologia , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos da radiação , Feminino , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/efeitos da radiação , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos da radiação , Masculino , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Atividade Motora/efeitos da radiação , Gravidez , Proteína Quinase C/metabolismo , Lesões Experimentais por Radiação/prevenção & controle , Ratos , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/efeitos da radiação , Tempo , Raios XRESUMO
Regeneration and growth that occur in the adult teleost retina have been helpful in identifying molecular and cellular mechanisms underlying cell proliferation and differentiation. Here, it is reported that S-phase cell number, in the ciliary marginal zone (CMZ) of the adult zebrafish retina, exhibits day-night variations with a mid-light phase peak. Oscillations persist for 24 h in constant darkness (DD), suggesting control by a circadian component. However, variations in the S-phase nuclei number were rapidly dampened and not present during and after a second day in DD. An ADPßS treatment significantly enhanced S-phase activity at night to mid-light levels, as assessed by in vivo BrdU incorporation in a 2-h interval. Moreover, daylight increase in S-phase cell number was completely abolished when extracellular nucleotide levels or their extracellular hydrolysis by ectonucleoside triphosphate diphosphohydrolases (NTPDases) were significantly disrupted or when a selective antagonist of purinergic P2Y1 receptors was intraocularly injected before BrdU exposure. Extracellular nucleotides and NTPDase action were also important for maintaining nocturnal low levels of S-phase activity in the CMZ. Finally, we showed that mRNAs of NTPDases 1, 2 (3 isoforms), and 3 as well as of P2Y1 receptor are present in the neural retina of zebrafish. NTPDase mRNA expression exhibited a 2-fold increment in light versus dark conditions as assessed by quantitative RT-PCR, whereas P2Y1 receptor mRNA levels did not show significant day-night variations. This study demonstrates a key role for nucleotides, principally ADP as a paracrine signal, as well as for NTPDases, the plasma membrane-bound enzymes that control extracellular nucleotide concentration, for inducing S-phase cell entry in the CMZ-normally associated with retinal growth-throughout the light-dark cycle.
Assuntos
Receptores Purinérgicos P2Y1/metabolismo , Retina/metabolismo , Fase S/fisiologia , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/metabolismo , Difosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Apirase/farmacologia , Diferenciação Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Relógios Circadianos/fisiologia , Inibidores Enzimáticos/farmacologia , Espaço Extracelular/metabolismo , Hexoquinase/farmacologia , Fotoperíodo , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Pirofosfatases/genética , Pirofosfatases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Purinérgicos P2Y1/genética , Retina/citologia , Retina/enzimologia , Fase S/efeitos dos fármacos , Transdução de Sinais , Tionucleotídeos/farmacologia , Peixe-ZebraRESUMO
Acute and long-term complications can occur in patients receiving radiation therapy. It has been suggested that cytoprotection might decrease the incidence and severity of therapy-related toxicity in these patients. Developing cerebellum is highly radiosensitive and for that reason it is a useful structure to test potential neuroprotective substances to prevent radiation induced abnormalities. Recent studies have shown that estrogen can rapidly modulate intracellular signalling pathways involved in cell survival. Thus, it has been demonstrated that estrogens mediate neuroprotection by promoting growth, cell survival and by preventing axonal pruning. The aim of this work was to evaluate the effect of the treatment with 17-ß-estradiol on the motor, structural and biochemical changes induced by neonatal ionizing radiation exposure, and to investigate the participation of nitric oxide and protein kinase C, two important intracellular messengers involved in neuronal activity. Our results show that perinatal chronic 17-ß-estradiol treatment partially protects against radiation-induced cerebellar disorganization and motor abnormalities. PKC and NOS activities could be implicated in its neuroprotective mechanisms. These data provide new evidence about the mechanisms underlying estrogen neuroprotection, which could have therapeutic relevance for patients treated with radiotherapy.
Assuntos
Dano Encefálico Crônico/tratamento farmacológico , Doenças Cerebelares/tratamento farmacológico , Estradiol/farmacologia , Fármacos Neuroprotetores/farmacologia , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/metabolismo , Animais , Animais Recém-Nascidos , Dano Encefálico Crônico/etiologia , Dano Encefálico Crônico/prevenção & controle , Doenças Cerebelares/etiologia , Doenças Cerebelares/prevenção & controle , Feminino , Raios gama , Masculino , Lesões Experimentais por Radiação/etiologia , Ratos , Ratos WistarRESUMO
This study investigated the participation of the hypothalamic endocannabinoid system in the response to lipopolysaccharide (LPS) challenge evaluating oxytocin (OXT) and tumor necrosis factor-alpha (TNF-alpha) plasma levels in vivo and their release from hypothalamic fragments in vitro. LPS increased OXT and TNF-alpha release through anandamide-activation of hypothalamic cannabinoid receptor CB(1,) since the antagonist AM251 blocked this effect. Anandamide, through its receptors, also increased hypothalamic nitric oxide (NO) which inhibited OXT release, ending the stimulatory effect of the endocannabinoid. Our findings reveal a hypothalamic interaction between oxytocin, endocannabinoid and NO-ergic systems providing a regulation of the hypothalamic-neurohypophyseal axis under basal and stress conditions.
Assuntos
Moduladores de Receptores de Canabinoides/metabolismo , Endocanabinoides , Hipotálamo/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Ocitocina/sangue , Fator de Necrose Tumoral alfa/sangue , Análise de Variância , Animais , Ácidos Araquidônicos/farmacologia , Benzamidas/farmacologia , Moduladores de Receptores de Canabinoides/antagonistas & inibidores , Moduladores de Receptores de Canabinoides/farmacologia , Carbamatos/farmacologia , Ensaio de Imunoadsorção Enzimática/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/metabolismo , Indóis/farmacologia , Masculino , Óxido Nítrico/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Radioimunoensaio/métodos , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismoRESUMO
The hypothalamo-neurohypophyseal system plays a role in homeostasis under a variety of stress conditions, including endotoxemia. Oxytocin (OXT) and vasopressin (VP) are important hormones synthesized by neurons in the hypothalamic paraventricular and supraoptic nuclei and released into different brain regions and from the neurohypophyseal terminals into the blood in response to many patho-physiological stimuli. However, the mechanism that controls OXT and VP secretion has not been fully elucidated. Nitric oxide (NO) is a known mediator that regulates the release of these hormones. The endocannabinoid system is a new intercellular system that modulates several neuroendocrine actions. Endocannabinoids (eCB) are released as retrograde messengers by many neurons, including hypothalamic magnocellular neurons and cannabinoid receptors are localized within these neurons, as well as in the anterior and posterior pituitary lobes, suggesting an eCB role in the production and release of OXT and VP. Lipopolysaccharide (LPS) injection is a model used as immune challenge. LPS causes a neuroendocrine response that is mediated by cytokines, tumor necrosis factor-alpha being one of them. We focused on NO and endocannabinoid system participation on OXT and VP production and secretion during basal and stress conditions and found that eCB affect basal OXT and VP secretion by acting differently at each level of the hypothalamo-neurohypophyseal system. After LPS, there is an increase in eCB synthesis that enhances OXT secretion.