RESUMO
Methylglyoxal (MG) is a by-product of glycolysis. In pathological conditions, particularly diabetes mellitus, this molecule is unbalanced, causing widespread protein glycation. In addition to protein glycation, other effects resulting from high levels of MG in the central nervous system may involve the direct modulation of GABAergic and glutamatergic neurotransmission, with evidence suggesting that the effects of MG may be related to behavioral changes and glial dysfunction. In order to evaluate the direct influence of MG on behavioral and biochemical parameters, we used a high intracerebroventricular final concentration (3 µM/µL) to assess acute effects on memory and locomotor behavior in rats, as well as the underlying alterations in glutamatergic and astroglial parameters. MG induced, 12 h after injection, a decrease in locomotor activity in the Open field and anxiolytic effects in rats submitted to elevated plus-maze. Subsequently, 36 h after surgery, MG injection also induced cognitive impairment in both short and long-term memory, as evaluated by novel object recognition task, and in short-term spatial memory, as evaluated by the Y-maze test. In addition, hippocampal glutamate uptake decreased and glutamine synthetase activity and glutathione levels diminished during seventy-two hours after infusion of MG. Interestingly, the astrocytic protein, S100B, was increased in the cerebrospinal fluid, accompanied by decreased hippocampal S100B mRNA expression, without any change in protein content. Taken together, these results may improve our understanding of how this product of glucose metabolism can induce the brain dysfunction observed in diabetic patients, as well as in other neurodegenerative conditions, and further defines the role of astrocytes in disease and therapeutics.
Assuntos
Astrócitos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Aldeído Pirúvico/toxicidade , Animais , Teste de Labirinto em Cruz Elevado , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Infusões Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Teste de Campo Aberto/efeitos dos fármacos , Aldeído Pirúvico/administração & dosagem , Ratos WistarRESUMO
Major depressive disorder (MDD) leads to pervasive changes in the health of afflicted patients. Despite advances in the understanding of MDD and its treatment, profound innovation is needed to develop fast-onset antidepressants with higher effectiveness. When acutely administered, the endogenous nucleoside guanosine (GUO) shows fast-onset antidepressant-like effects in several mouse models, including the olfactory bulbectomy (OBX) rodent model. OBX is advocated to possess translational value and be suitable to assess the time course of depressive-like behavior in rodents. This study aimed at investigating the long-term behavioral and neurochemical effects of GUO in a mouse model of depression induced by bilateral bulbectomy (OBX). Mice were submitted to OBX and, after 14 days of recovery, received daily (ip) administration of 7.5 mg/kg GUO or 40 mg/kg imipramine (IMI) for 45 days. GUO and IMI reversed the OBX-induced hyperlocomotion and recognition memory impairment, hippocampal BDNF increase, and redox imbalance (ROS, NO, and GSH levels). GUO also mitigated the OBX-induced hippocampal neuroinflammation (IL-1, IL-6, TNF-α, INF-γ, and IL-10). Brain microPET imaging ([18F]FDG) shows that GUO also prevented the OBX-induced increase in hippocampal FDG metabolism. These results provide additional evidence for GUO antidepressant-like effects, associated with beneficial neurochemical outcomes relevant to counteract depression.
RESUMO
Early life events lead to behavioral and neurochemical changes in adulthood. The aim of this study is to verify the effects of neonatal handling on spatial memory, nitric oxide (NO) production, antioxidant enzymatic activities and DNA breaks in the hippocampus of male and female adult rats. Litters of rats were non-handled or handled (10 min/day, days 1-10 after birth). In adulthood they were subjected to a Morris water maze or used for biochemical evaluations. Female handled rats showed impairment in spatial learning. They also showed decreased NO production, while no effects were observed in these parameters in male rats. No effects were observed on the number of hippocampal NADPH diaphorase positive cells. In the Comet Assay, male handled rats showed increased DNA breaks index when compared to non-handled ones. We conclude that neonatal handling impairs learning performance in a sex-specific manner, what may be related to NO decreased levels.
Assuntos
Quebras de DNA , Manobra Psicológica , Hipocampo/metabolismo , Memória , Óxido Nítrico/biossíntese , Percepção Espacial , Animais , Catalase/metabolismo , Ensaio Cometa , Feminino , Glutationa Peroxidase/metabolismo , Masculino , Aprendizagem em Labirinto , NADPH Desidrogenase/metabolismo , Ratos , Ratos Wistar , Fatores Sexuais , Superóxido Dismutase/metabolismoRESUMO
Interactions on neurotransmitter systems in the reward pathways may explain the high frequency of combined use of alcohol and cigarettes in humans. In this study, we evaluated some behavioral and neurochemical changes promoted by chronic exposure to alcohol and cigarette smoke in rats. Adult rats were administered with 2 g/kg alcohol (v.o.) or/and inhaled the smoke from 6 cigarettes, twice/day, for 30 days. Behavioral tests were performed 3 h after the alcohol administration and 1 h after the last exposure to cigarette smoke in the morning. Cerebrospinal fluid was collected for glutamate determination and the hippocampus was dissected for GABAA and NMDA receptor subunits mRNA expression determination. Results showed that the combined use of alcohol and cigarette smoke (ALTB) in rats increased the locomotor activity and all interventions decreased anxiety-like behaviors. Despite being on a short-term withdrawal, the cigarette smoke exposure decreased the percentage of open arm entries in the elevated plus maze test, which was prevented by combined use with alcohol. Even though GABAA and glutamate receptor subunits expression did not change in the hippocampus, glutamate levels were significantly higher in the cerebrospinal fluid from ALTB rats. Therefore, we showed that the combined use of alcohol and cigarette maintained a psychostimulant effect after a short-term withdrawal that was associated with the elevated glutamatergic activity. The combined use also prevented anxiety-like signs in cigarette smoke exposure rats, decreasing an adverse effect caused by nicotine withdrawal. These results could explain, in part, the elevated frequency of combined use of these two drugs of abuse in humans.
Assuntos
Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Fumar Cigarros , Etanol/farmacologia , Ácido Glutâmico/líquido cefalorraquidiano , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Quimioterapia Combinada , Etanol/administração & dosagem , Ácido Glutâmico/efeitos dos fármacos , Aprendizagem em Labirinto , RNA Mensageiro , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacosRESUMO
Amyloid-ß oligomers (AßOs) toxicity causes mitochondrial dysfunction, leading to synaptic failure in Alzheimer's disease (AD). Considering presynaptic high energy demand and tight Ca2+ regulation, impairment of mitochondrial function can lead to deteriorated neural activity and cell death. In this study, an AD mouse model induced by ICV (intracerebroventricular) injection of AßOs was used to investigate the toxicity of AßOs on presynaptic function. As a therapeutic approach, GUO (guanosine) was given by oral route to evaluate the neuroprotective effects on this AD model. Following 24 h and 48 h from the model induction, behavioral tasks and biochemical analyses were performed, respectively. AßOs impaired object recognition (OR) short-term memory and reduced glutamate uptake and oxidation in the hippocampus. Moreover, AßOs decreased spare respiratory capacity, reduced ATP levels, impaired Ca2+ handling, and caused mitochondrial swelling in hippocampal synaptosomes. Guanosine crossed the BBB, recovered OR short-term memory, reestablished glutamate uptake, recovered mitochondrial Ca2+ homeostasis, and partially prevented mitochondrial swelling. Therefore, this endogenous purine presented a neuroprotective effect on presynaptic mitochondria and should be considered for further studies in AD models.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Cálcio/metabolismo , Guanosina/farmacologia , Homeostase , Mitocôndrias/metabolismo , Neuroproteção/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Peptídeos beta-Amiloides/administração & dosagem , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Guanosina/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Sinaptossomos/metabolismo , Sinaptossomos/ultraestruturaRESUMO
OBJECTIVE: Exposure to artificial sweeteners, such as aspartame, during childhood and adolescence has been increasing in recent years. However, the safe use of aspartame has been questioned owing to its potentially harmful effects on the developing brain. The aim of this study was to test whether the chronic consumption of aspartame during adolescence leads to a depressive-like phenotype and to investigate the possible mechanisms underlying these behavioral changes. METHODS: Adolescent male and female rats were given unlimited access to either water, solutions of aspartame, or sucrose in their home cages from postnatal day 21 to 55. RESULTS: Forced swim test revealed that both chronic aspartame and sucrose intake induced depressive-like behaviord, which was more pronounced in males. Additionally, repeated aspartame intake was associated with increased cerebrospinal fluid (CSF) aspartate levels, decreased hippocampal neurogenesis, and reduced activation of the hippocampal leptin signaling pathways in males. In females, we observed a main effect of aspartame: reducing PI3K/AKT one of the brain-derived neurotrophic factor pathways; aspartame also increased CSF aspartate levels and decreased the immunocontent of the GluN2A subunit of the N-methyl-d-aspartic acid receptor. CONCLUSION: The findings revealed that repeated aspartame intake during adolescence is associated with a depressive-like phenotype and changes in brain plasticity. Interestingly, males appear to be more vulnerable to the adverse neurometabolic effects of aspartame than females, demonstrating a sexually dimorphic response. The present results highlighted the importance of understanding the effects caused by the constant use of this artificial sweetener in sensitive periods of development and contribute to regulation of its safe use.
Assuntos
Aspartame , Fosfatidilinositol 3-Quinases , Edulcorantes , Animais , Aspartame/toxicidade , Feminino , Masculino , Fenótipo , Ratos , Sacarose , Edulcorantes/toxicidadeRESUMO
Glutamate is an excitatory neurotransmitter involved in neuronal plasticity and neurotoxicity. Chronic stress produces several physiological changes on the spinal cord, many of them presenting sex-specific differences, which probably involve glutamatergic system alterations. The aim of the present study was to verify possible effects of exposure to chronic restraint stress and 17beta-estradiol replacement on [3H]-glutamate release and uptake in spinal cord synaptosomes of ovariectomized (OVX) rats. Female rats were subjected to OVX, and half of the animals received estradiol replacement. Animals were subdivided in controls and chronically stressed. Restraint stress or estradiol had no effect on [3H]-glutamate release. The chronic restraint stress promoted a decrease and 17beta-estradiol induced an increase on [3H]-glutamate uptake, but the uptake observed in the restraint stress +17beta-estradiol group was similar to control. Furthermore, 17beta-estradiol treatment caused a significant increase in the immunocontent of the three glutamate transporters present in spinal cord. Restraint stress had no effect on the expression of these transporters, but prevented the 17beta-estradiol effect. We suggest that changes in the glutamatergic system are likely to take part in the mechanisms involved in spinal cord plasticity following repeated stress exposure, and that 17beta-estradiol levels may affect chronic stress effects in this structure.
Assuntos
Estradiol/farmacologia , Ácido Glutâmico/metabolismo , Restrição Física , Medula Espinal/efeitos dos fármacos , Estresse Psicológico/metabolismo , Animais , Doença Crônica , Transportador 1 de Aminoácido Excitatório/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Transportador 3 de Aminoácido Excitatório/metabolismo , Feminino , Ovariectomia , Ratos , Ratos Wistar , Medula Espinal/metabolismo , Sinaptossomos/metabolismoRESUMO
The hypothalamus is a crucial integrative center in the central nervous system, responsible for the regulation of homeostatic activities, including systemic energy balance. Increasing evidence has highlighted a critical role of astrocytes in orchestrating hypothalamic functions; they participate in the modulation of synaptic transmission, metabolic and trophic support to neurons, immune defense, and nutrient sensing. In this context, disturbance of systemic energy homeostasis, which is a common feature of obesity and the aging process, involves inflammatory responses. This may be related to dysfunction of hypothalamic astrocytes. In this regard, the aim of this study was to evaluate the neurochemical properties of hypothalamic astrocyte cultures from newborn, adult, and aged Wistar rats. Age-dependent changes in the regulation of glutamatergic homeostasis, glutathione biosynthesis, amino acid profile, glucose metabolism, trophic support, and inflammatory response were observed. Additionally, signaling pathways including nuclear factor erythroid-derived 2-like 2/heme oxygenase-1 p38 mitogen-activated protein kinase, nuclear factor kappa B, phosphatidylinositide 3-kinase/Akt, and leptin receptor expression may represent putative mechanisms associated with the cellular alterations. In summary, our findings indicate that as age increases, hypothalamic astrocytes remodel and exhibit changes in their neurochemical properties. This process may play a role in the onset and/or progression of metabolic disorders.
Assuntos
Envelhecimento/metabolismo , Astrócitos/metabolismo , Hipotálamo/metabolismo , Aminoácidos/metabolismo , Animais , Astrócitos/patologia , Forma Celular , Células Cultivadas , Heme Oxigenase-1/metabolismo , Inflamação/patologia , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Neurogênese , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos Wistar , Receptores para Leptina/metabolismo , Transdução de SinaisRESUMO
Adenosine acting on A(1) receptors has been related with neuroprotective and neuromodulatory actions, protection against oxidative stress and decrease of anxiety and nociceptive signaling. Previous studies demonstrated an inhibition of the enzymes that hydrolyze ATP to adenosine in the rat central nervous system after hyperthyroidism induction. Manifestations of hyperthyroidism include increased anxiety, nervousness, high O(2) consumption and physical hyperactivity. Here, we investigated the effects of administration of a specific agonist of adenosine A(1) receptor (N(6)-cyclopentyladenosine; CPA) on nociception, anxiety, exploratory response, locomotion and brain oxidative stress of hyperthyroid rats. Hyperthyroidism was induced by daily intraperitoneal injections of l-thyroxine (T4) for 14 days. Nociception was assessed with a tail-flick apparatus and exploratory behavior, locomotion and anxiety were analyzed by open-field and plus-maze tests. We verified the total antioxidant reactivity (TAR), lipid peroxide levels by the thiobarbituric acid reactive species (TBARS) reaction and the free radicals content by the DCF test. Our results demonstrated that CPA reverted the hyperalgesia induced by hyperthyroidism and decreased the exploratory behavior, locomotion and anxiety in hyperthyroid rats. Furthermore, CPA decreased lipid peroxidation in hippocampus and cerebral cortex of control rats and in cerebral cortex of hyperthyroid rats. CPA also increased the total antioxidant reactivity in hippocampus and cerebral cortex of control and hyperthyroid rats, but the production of free radicals verified by the DCF test was changed only in cerebral cortex. These results suggest that some of the hyperthyroidism effects are subjected to regulation by adenosine A(1) receptor, demonstrating the involvement of the adenosinergic system in this pathology.
Assuntos
Agonistas do Receptor A1 de Adenosina , Adenosina/análogos & derivados , Comportamento Exploratório/efeitos dos fármacos , Hipertireoidismo/metabolismo , Atividade Motora/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Adenosina/farmacologia , Análise de Variância , Animais , Ansiedade/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Exploratório/fisiologia , Masculino , Atividade Motora/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Limiar da Dor/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Receptor A1 de Adenosina/metabolismo , Estatísticas não Paramétricas , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Pleasant and unpleasant flavors and odors can modulate pain perception, and the efficacy of sweet flavors in reducing pain seems to be related to its hedonic value. Chronic variate stress paradigm is a model of depression, and is suggested to induce anhedonia. We observed previously that lithium may prevent behavioral and neurochemical alterations induced by chronic stress; so we hypothesized that chronically stressed animals may present different nociceptive response to pleasant and unpleasant tastes that could be prevented by lithium treatment. Adult male Wistar rats were divided into four groups, control and stressed, treated or not with lithium. A Chronic Variate Stress paradigm was used, and lithium was added to the chow. After 40 days of treatment, the tail flick latency of the animals was evaluated, and rats were immediately placed in a box with access to a 5% acetic acid solution (acid flavor). After 5 min, tail flick latency was measured again. On the following day, animals were submitted to the same procedure, with the substitution of acetic acid by condensed sweet milk (sweet flavor). The stressed group was the only group who did not present analgesia after sweet taste exposition. All groups, except the control group, presented increased tail flick latency after exposition to the acid flavor. These results indicate that pleasant and unpleasant flavors present different relevance for the induction of antinociception in stressed animals, and the absence of sweet flavor-induced analgesia may represent an anhedonic effect of the chronic variate stress paradigm. On the other hand, perception of different flavors may be more prominent in animals treated with lithium.
Assuntos
Lítio/farmacologia , Dor/psicologia , Estresse Psicológico/psicologia , Paladar/fisiologia , Animais , Masculino , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacosRESUMO
Several studies have shown that high corticosteroid hormone levels increase neuronal vulnerability. Here we evaluate the consequences of in vivo acute or repeated restraint stress on cellular viability in rat hippocampal slices suffering an in vitro model of ischemia. Cellular injury was quantified by measuring lactate dehydrogenase (LDH) and neuron-specific enolase released into the medium. Acute stress did not affect cellular death when oxygen and glucose deprivation (OGD) was applied both immediately or 24h after restraint. The exposure to OGD, followed by reoxygenation, resulted in increased LDH in the medium. Repeated stress potentiated the effect of OGD both, on LDH and neuron-specific enolase released to the medium. There was no effect of repeated stress on the release of S100B, an astrocytic protein. Additionally, no effect of repeated stress was observed on glutamate uptake by the tissue. These results suggest that repeated stress increases the vulnerability of hippocampal cells to an in vitro model of ischemia, potentiating cellular damage, and that the cells damaged by the exposure to repeated stress+OGD are mostly neurons. The uptake of glutamate was not observed to participate in the mechanisms responsible for rendering the neurons more susceptible to ischemic damage after repeated stress.
Assuntos
Glucose/deficiência , Hipocampo/metabolismo , Hipóxia , Estresse Fisiológico/metabolismo , Análise de Variância , Animais , Ensaio de Imunoadsorção Enzimática/métodos , Ácido Glutâmico/metabolismo , Hipocampo/patologia , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Masculino , Fatores de Crescimento Neural/metabolismo , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Wistar , Restrição Física/métodos , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/metabolismo , Sódio/farmacologia , Fatores de TempoRESUMO
It has been reported that animals submitted to repeated restraint stress present various adaptation responses which are dependent on the sex. These adaptations include changes in nociception and adenine nucleotide hydrolysis. In this study, we report the effect of chronic administration of a gonadal steroid (17beta-estradiol) on ATP, ADP and AMP hydrolysis in spinal cord synaptosomes of adult ovariectomized (OVX) Wistar rats submitted to repeated restraint stress over 40 days. We also measured nociceptive threshold in these animals using the tail-flick test. The results show that tail-flick latencies were decreased in both stressed groups, OVX and OVX rats receiving estradiol replacement therapy, indicating reduced nociceptive threshold after exposure to repeated stress. Repeated restraint stress caused no effect on ATPase or ADPase activities. On the other hand, AMP hydrolysis in spinal cord synaptosomes from repeatedly stressed rats was decreased in OVX rats compared to non-stressed OVX ones, indicating reduced extracellular adenosine production; this effect was reversed by hormonal replacement. These observations suggest that nociceptive sensitivity to noxious stimuli is affected by repeated stress and that modulation of neurotransmission by adenine nucleotides in spinal cord may be altered by the interaction of sexual hormones and psychological factors, such as exposure to stress.
Assuntos
Adenosina Trifosfatases/metabolismo , Estradiol/administração & dosagem , Nociceptores/fisiopatologia , Medula Espinal/citologia , Estresse Fisiológico/enzimologia , Sinaptossomos/efeitos dos fármacos , Difosfato de Adenosina/metabolismo , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Análise de Variância , Animais , Feminino , Hidrólise/efeitos dos fármacos , Ovariectomia/métodos , Medição da Dor/métodos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Restrição Física/métodos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Sinaptossomos/enzimologiaRESUMO
AIM: To evaluate the nutritional status and its association with proinflammatory cytokines in children with chronic liver disease. METHODS: We performed a cross-sectional study with 43 children and adolescents, aged 0 to 17 years, diagnosed with chronic liver disease. All patients regularly attended the Pediatric Hepatology Unit and were under nutritional follow up. The exclusion criteria were fever from any etiology at the time of enrollment, inborn errors of the metabolism and any chronic illness. The severity of liver disease was assessed by Child-Pugh, Model for End-stage Liver Disease (MELD) and Pediatric End Stage Liver Disease (PELD) scores. Anthropometric parameters were height/age, body mass index/age and triceps skinfold/age according to World Health Organization standards. The cutoff points for nutritional status were risk of malnutrition (Z-score < -1.00) and malnutrition (Z-score < -2.00). Interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α levels were assessed by commercial ELISA kits. For multivariate analysis, linear regression was applied to assess the association between cytokine levels, disease severity and nutritional status. RESULTS: The median (25(th)-75(th) centile) age of the study population was 60 (17-116)-mo-old, and 53.5% were female. Biliary atresia was the main cause of chronic liver disease (72%). With respect to Child-Pugh score, cirrhotic patients were distributed as follows: 57.1% Child-Pugh A, a mild presentation of the disease, 34.3% Child-Pugh B, a moderate stage of cirrhosis and 8.6% Child-Pugh C, were considered severe cases. PELD and MELD scores were only above the cutoff point in 5 cases. IL-6 values ââwere increased in patients at nutritional risk (34.9%) compared with those who were well-nourished [7.12 (0.58-34.23) pg/mL vs 1.63 (0.53-3.43) pg/mL; P = 0.02], correlating inversely with triceps skinfold-for-age z-score (rs = -0.61; P < 0.001). IL-6 levels were associated with liver disease severity assessed by Child-Pugh score (P = 0.001). This association remained significant after adjusting for nutritional status in a linear regression model. CONCLUSION: High IL-6 levels were found in children with chronic liver disease at nutritional risk. Inflammatory activity may be related to nutritional status deterioration in these patients.
Assuntos
Citocinas/sangue , Mediadores da Inflamação/sangue , Hepatopatias/diagnóstico , Desnutrição/etiologia , Estado Nutricional , Adolescente , Fatores Etários , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Criança , Fenômenos Fisiológicos da Nutrição Infantil , Pré-Escolar , Doença Crônica , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lactente , Interleucina-6/sangue , Modelos Lineares , Hepatopatias/sangue , Hepatopatias/etiologia , Hepatopatias/imunologia , Hepatopatias/fisiopatologia , Masculino , Desnutrição/sangue , Desnutrição/diagnóstico , Desnutrição/imunologia , Desnutrição/fisiopatologia , Análise Multivariada , Avaliação Nutricional , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Regulação para CimaRESUMO
Stress responses cover a wide range of physiological changes, including alterations in the perception of and response to pain. Animals submitted to repeated stress present altered nociception and this effect is part of this process of adaptation; in addition pleasant and unpleasant experiences with tastes and odors have been shown to affect distinct behavioral aspects, such as pain perception. The aim of the present study is to verify the responses of repeatedly stressed rats (1 h of daily immobilization during 40 days) to pleasant and unpleasant tastes on nociception, when compared to control animals. An increase in the tail-flick latency (TFL) was observed 5 min after exposure to a sweet taste in the control group, whereas no effect was observed in chronically stressed animals. When submitted to an unpleasant taste (5% acetic acid), the chronically stressed group presented an increase in TFL, whereas no effect was observed in the control group. In conclusion, chronically stressed animals present different nociceptive responses to sweet and acid tastes; although control animals suitably respond to a sweet stimulus, stressed animals seem to be more apt to react to the unpleasant stimulus.
Assuntos
Analgesia/psicologia , Medição da Dor , Dor/fisiopatologia , Estresse Psicológico/fisiopatologia , Paladar , Adaptação Fisiológica , Animais , Nível de Alerta/fisiologia , Doença Crônica , Imobilização , Masculino , Nociceptores/fisiologia , Dor/psicologia , Ratos , Ratos Wistar , Estresse Psicológico/psicologiaRESUMO
Hyperactivity of the stress response has long been recognized as maladaptive. The hippocampus, a brain structure important in mediating this response, is known to be affected by chronic stress, a situation reported to induce changes in adenine nucleotide hydrolysis in the rat. The enzymes catalyzing the hydrolysis of ATP to adenosine in the synaptic cleft are thought to have a role in modulating and controlling synaptic transmission. This study aimed to investigate the effect of acute and repeated restraint stress on the ATP, ADP and AMP hydrolyses in rat hippocampal synaptosomes. Adult male Wistar rats were submitted to acute or repeated (15 and 40 days) stress, and ATPase-ADPase, and 5'nucleotidase activities were assayed in the hippocampal synaptosomal fraction. Acute stress induced increased hydrolyses of ATP (21%), ADP (21%) and AMP (40%). In contrast, ATP hydrolysis was increased by 20% in repeatedly stressed rats, without changes in the ADP or AMP hydrolysis. The same results were observed after 15 or 40 days of stress. Therefore, acute stress increases ATP diphosphohydrolase activity which, in association with 5'-nucleotidase, contributes to the elimination of ATP and provides extracellular adenosine. Interestingly, increased ecto-ATPase activity in response to chronic stress reveals an adaptation to this treatment.
Assuntos
Adenosina Trifosfatases/metabolismo , Hipocampo/enzimologia , Estresse Fisiológico/enzimologia , Sinaptossomos/enzimologia , Doença Aguda , Animais , Doença Crônica , Ativação Enzimática/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
Morphine exposure during the neonatal period can promote changes in pain signaling pathways that can be expressed as an increased nociceptive response in adult life. Glutamate is the major excitatory neurotransmitter in primary afferent terminals and plays a critical role in normal spinal excitatory synaptic transmission. Considering the importance of a better understanding of the mechanisms that underlie nociceptive changes throughout the life course, the aim of this study was investigate the effects of repeated morphine administration at postnatal days 8 (P8) to 14 (P14) on glutamate uptake in spinal synaptosomes at P30 and P60. The morphine group showed decreased [3H]-glutamate uptake as compared to control groups in both P30 and P60. These findings suggest that morphine exposure in early life leads to changes in glutamatergic signaling at least until the 60th day of age, which may lead to increased levels of glutamate in the spinal synaptic cleft and, consequently, an increased nociceptive response in adult life. Thus, this study highlights the importance of conducting research in this field to provide a comprehensive knowledge of the long-term effects of early-life morphine treatment on nociceptive pathways.
Assuntos
Envelhecimento/metabolismo , Ácido Glutâmico/metabolismo , Morfina/administração & dosagem , Neurônios/metabolismo , Medula Espinal/metabolismo , Sinaptossomos/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Masculino , Neurônios/efeitos dos fármacos , Neurotransmissores/metabolismo , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacosRESUMO
Changes in transport, receptors and production of extracellular adenosine have been observed after induction of hyperthyroidism. Adenosine is associated with inhibitory actions such as reduction in release of excitatory neurotransmitters and antinociception at spinal site. In contrast, ATP acts as an excitatory neurotransmitter and produces pronociceptive actions. ATP may be completely hydrolyzed to adenosine by an enzyme chain constituted by an ATP diphosphohydrolase and an ecto-5'-nucleotidase, as previously described in the spinal cord. Thus, we now investigated the effects of the hyperthyroidism on adenine nucleotide hydrolysis in the spinal cord and verified the nociceptive response in this pathology during different phases of development. Hyperthyroidism was induced in male Wistar rats, aged 5, 60 and 330 days by daily intraperitoneal injections of L-thyroxine (T4) for 14 days. Nociception was assessed with a tail-flick apparatus. Rats starting the treatment aged 5 days demonstrated a significant increase in ADP and AMP hydrolysis and increased tail-flick latency (TFL). In contrast, in the spinal cord from hyperthyroid rats aged 60 and 330 days old, the hydrolysis of ATP, ADP and AMP were significantly decreased. Accordingly, the tail-flick latency was decreased, indicating a hyperalgesic response. These results suggest the involvement of ecto-nucleotidases in the control of the hyperthyroidism-induced nociceptive response in rats at distinct developmental stages.
Assuntos
Adenosina Trifosfatases/metabolismo , Hipertireoidismo/enzimologia , Hipertireoidismo/fisiopatologia , Dor/fisiopatologia , Medula Espinal/enzimologia , Sinaptossomos/enzimologia , Trifosfato de Adenosina/metabolismo , Animais , Hipertireoidismo/induzido quimicamente , Masculino , Medição da Dor , Ratos , Medula Espinal/anatomia & histologia , Medula Espinal/crescimento & desenvolvimento , Sinaptossomos/metabolismo , Tiroxina/toxicidadeRESUMO
Purinergic system exerts a significant influence on the modulation of pain pathways at the spinal site. Adenosine has antinociceptive properties in experimental and clinical situations, while ATP exerts pronociceptive actions in different pain models. In this study we investigated the hydrolysis of ATP to adenosine in synaptosomes from spinal cord in parallel with the nociceptive response of rats at different ages after hypothyroidism induction. Hypothyroidism elicited a significant increase in AMP hydrolysis to adenosine in synaptosomes from spinal cord of rats subjected to neonatal hypothyroidism and in 420-day-old rats submitted to thyroidectomy. Accordingly, these rats presented an analgesic response as a consequence of hypothyroidism. In contrast, the ATP hydrolysis was decreased in the spinal cord of 60-day-old hypothyroid rats in parallel with a significant increase in nociceptive response. These results indicate the involvement of adenine nucleotides in the control of the hypothyroidism-induced nociceptive response during development.
Assuntos
Nucleotídeos de Adenina/metabolismo , Hipotireoidismo/metabolismo , Dor/metabolismo , Medula Espinal/citologia , Sinaptossomos/metabolismo , Fatores Etários , Animais , Masculino , Medição da Dor , Ratos , Ratos WistarRESUMO
Neurochemical gender-specific effects have been observed following chronic stress. The aim of this study was to verify the effects of chronic variable stress on free radical production (evaluated by DCF test), lipoperoxidation (evaluated by TBARS levels), and total antioxidant reactivity (TAR) in three distinct structures of brain: hippocampus, cerebral cortex and hypothalamus of female rats, and to evaluate whether the replacement with estradiol in female rats exerts neuroprotection against oxidative stress. Results demonstrate that chronic stress had a structure-specific effect upon lipid peroxidation, since TBARS increased in hypothalamus homogenates of stressed animals, without alterations in the other structures analyzed. Estradiol replacement was able to counteract this effect. In hippocampus, estradiol induced a significant increase in TAR. No differences in DCF levels were observed. In conclusion, the hypothalamus is more susceptible to oxidative stress in female rats submitted to chronic variable stress, and this effect is prevented by estradiol treatment.
Assuntos
Estradiol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Fisiológico/tratamento farmacológico , Animais , Doença Crônica , Estradiol/uso terapêutico , Feminino , Ovariectomia , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Estresse Fisiológico/metabolismoRESUMO
Behavioral and neurochemical gender-specific effects have been observed following repeated stress. The aim of this study is to verify the effects of repeated restraint stress on free radical production (evaluated by DCF test), lipoperoxidation (evaluated by TBARS levels), and total antioxidant reactivity (TAR) in the spinal cord of male and female rats. Results demonstrate no effect on lipoperoxidation; chronic stress decreased TAR both in male and female spinal cord. In addition, gender differences were observed both in TAR and in the production of free radicals, both being increased in females. These results may be relevant to the gender-specific differences observed after exposure to repeated stress.