RESUMO
AIM: To assess the incidence of glucose metabolism disorders, administered hypoglycemic therapy and its effectiveness in a cohort of patients with previously diagnosed diabetes mellitus (DM) hospitalized for scheduled lower limb joint arthroplasty. MATERIALS AND METHODS: The study included 502 patients. Medical history, information about previously diagnosed DM and prescribed hypoglycemic therapy were collected in all patients according to medical documentation, as well as according to the patients' survey. Within the preoperative examination, the glucose level was measured, and in patients with previously diagnosed diabetes, measuremaent of the HbA1c level was recommended. RESULTS: The study population included 180 (35.9%) males and 322 females (64.1%). Among them, 99 (19.7%) patients had disorders of glucose metabolism [type 1 diabetes - 1 (0.2%) patient, type 2 diabetes - 90 (17.9%) patients, impaired glucose tolerance (IGT) - 8 (1.6%) patients]. In 8 patients, type 2 diabetes was newly diagnosed during the preoperative examination. HbA1c was measured before hospitalization in 26 patients with diabetes, the mean level was 7.0±1.4%. Regarding the analysis of hypoglycemic therapy, almost half of the patients with DM - 47 (47.5%) - received metformin monotherapy, 8 patients with IGT and 8 patients with newly diagnosed DM did not receive any drug therapy. Target glycemic levels during therapy were achieved in 36 (36.4%) patients, and target HbA1c levels were achieved in 21 patients. CONCLUSION: The cohort of patients hospitalized for elective lower limb joint arthroplasty is characterized by a relatively high incidence of glucose metabolism disorders, and in some patients, DM was newly diagnosed during the preoperative examination. Metformin is most often used as hypoglycemic therapy, and the target values of glycemia during treatment were achieved in less than half of the patients. The monitoring of the level of glycated hemoglobin is low and requires additional population analysis in order to determine the causes and optimize the strategy of patient management.
Assuntos
Hemoglobinas Glicadas , Hipoglicemiantes , Humanos , Masculino , Feminino , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , Hemoglobinas Glicadas/metabolismo , Hemoglobinas Glicadas/análise , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicemia/metabolismo , Transtornos do Metabolismo de Glucose/etiologia , Transtornos do Metabolismo de Glucose/epidemiologia , Transtornos do Metabolismo de Glucose/sangue , Federação Russa/epidemiologia , Extremidade Inferior/cirurgia , Artroplastia do Joelho/métodos , Procedimentos Cirúrgicos Eletivos/métodosRESUMO
Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations. Mice with the G93A human SOD1 mutation have altered electron transport enzymes, and expression of the mutant enzyme in vitro results in a loss of mitochondrial membrane potential and elevated cytosolic calcium concentration. Mitochondrial dysfunction may lead to ATP depletion, which may contribute to cell death. If this is true, then buffering intracellular energy levels could exert neuroprotective effects. Creatine kinase and its substrates creatine and phosphocreatine constitute an intricate cellular energy buffering and transport system connecting sites of energy production (mitochondria) with sites of energy consumption, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore. We found that oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice, and it protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administration may be a new therapeutic strategy for ALS.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Creatina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Alanina/genética , Alanina/fisiologia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Creatina/administração & dosagem , Creatina/metabolismo , Modelos Animais de Doenças , Glicina/genética , Glicina/fisiologia , Humanos , Camundongos , Camundongos Transgênicos , Atividade Motora , Músculo Esquelético/fisiopatologia , Neurônios/citologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/fisiologia , Superóxido Dismutase-1 , Tirosina/análogos & derivados , Tirosina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The high mortality rate from ovarian cancer is due to the asymptomatic nature of the course of the disease, which leads to the diagnosis of ovarian cancer in later stages. The sodium-dependent phosphate transporter NaPi2b encoded by SLC34A2 gene is expressed in 80-90% of epithelial ovarian cancers and used as a target for therapeutic antibodies XMT-1536, and XMT-1592, which are derived from MX35 antibodies and used in clinical trials for the treatment of ovarian and lung cancers. In this work, we aimed to evaluate NaPi2b as a molecular marker for diagnostics and predicting the course and outcome of ovarian cancer disease. Quantitative analysis of SLC34A2 gene expression in ovarian tumor tissue was performed at the level of transcription and translation using real-time PCR, droplet digital PCR and Western blot analysis respectively. Statistical analysis was performed taking into account various clinicopathological characteristics of the ovarian cancer patients, including the stage of the disease, the tumor grade, the applying of neoadjuvant chemotherapy and the presence of ascites. In this work, we demonstrated that the expression of the human NaPi2b (hNaPi2b) transporter is downregulated in the tumors of patients receiving neoadjuvant therapy and during the development of disease. The data suggest that the level of expression of the SLC34A2 gene can serve as a potential marker for the monitoring and predicting responses to neoadjuvant and targeted therapy in patients with ovarian cancer.
RESUMO
PURPOSE: Conventional imaging modalities are presently recommended for the detection of liver metastases. However, the presence of liver micrometastases is a major diagnostic problem. It has been known that micrometastases could be associated with changes in the liver blood flow. METHODS: We examined several parameters by color Doppler ultrasound to estimate hepatic artery flow in 30 patients without and 17 patients with liver metastases from colon cancer. RESULTS: Mean values of hepatic artery diameter (4.25 + or - 0.81 mm in patients with liver metastases were not statistically different from those in patients without metastases (3.98 + or - 0.81). Patients with liver metastasis had significantly higher (p=0.007) mean values of systolic speed (61.33 + or - 30.01 cm/s) in comparison to patients without metastasis (41.38 + or - 16 cm/s). CONCLUSION: Based on these results we suggest that color Doppler examination can be an additional quick noninvasive method in the detection of circulatory changes in the estimation of liver metastases.
Assuntos
Neoplasias Colorretais/diagnóstico por imagem , Artéria Hepática/diagnóstico por imagem , Circulação Hepática , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Velocidade do Fluxo Sanguíneo , Antígeno Carcinoembrionário/sangue , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Ultrassonografia/métodosRESUMO
In the absence of extracellular stimulation the adaptor protein growth factor receptor-bound protein (Grb2) and the phospholipase Plcγ1 compete for the same binding site on fibroblast growth factor receptor 2 (FGFR2). Reducing cellular Grb2 results in upregulation of Plcγ1 and depletion of the phospholipid PI(4,5)P2. The functional consequences of this event on signaling pathways are unknown. We show that the decrease in PI(4,5)P2 level under non-stimulated conditions inhibits PTEN activity leading to the aberrant activation of the oncoprotein Akt. This results in excessive cell proliferation and tumor progression in a xenograft mouse model. As well as defining a novel mechanism of Akt phosphorylation with important therapeutic consequences, we also demonstrate that differential expression levels of FGFR2, Plcγ1 and Grb2 correlate with patient survival. Oncogenesis through fluctuation in the expression levels of these proteins negates extracellular stimulation or mutation and defines them as novel prognostic markers in ovarian cancer.
Assuntos
Proteína Adaptadora GRB2/genética , Proteína Oncogênica v-akt/genética , Neoplasias Ovarianas/genética , PTEN Fosfo-Hidrolase/genética , Fosfolipase C gama/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Animais , Carcinogênese/genética , Proliferação de Células/genética , Feminino , Proteína Adaptadora GRB2/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Neoplasias Ovarianas/patologia , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositóis/metabolismo , Fosfolipase C gama/biossíntese , Prognóstico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/biossíntese , Transdução de SinaisRESUMO
Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H(2)O(2)) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2-3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2, 5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.
Assuntos
Convulsivantes/toxicidade , Glutationa Peroxidase/genética , Intoxicação por MPTP/genética , Malonatos/toxicidade , Propionatos/toxicidade , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/análise , Animais , Química Encefálica/efeitos dos fármacos , Química Encefálica/genética , Catecóis/análise , Corpo Estriado/química , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Modelos Animais de Doenças , Dopaminérgicos/farmacologia , Feminino , Radicais Livres/metabolismo , Glutationa/metabolismo , Heterozigoto , Ácido Homovanílico/análise , Homozigoto , Doença de Huntington/genética , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Nitrocompostos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Doença de Parkinson Secundária/genética , Tirosina/análogos & derivados , Tirosina/análiseRESUMO
Recent observations confirm the participation of acid phospholipids in protein translocation. The hypothesis proposed coupled protein translocation with transmembrane movement of acid phospholipids, their metabolism as a precursor of cell envelope components and recycling. These factors ensure the unidirectional vector value of the secretion, restoration of the membrane site competent for protein translocation and its self-organization.
Assuntos
Proteínas de Bactérias/metabolismo , Membrana Celular/metabolismo , Lipídeos de Membrana/fisiologia , Fosfolipídeos/fisiologia , Bactérias/metabolismo , Transporte Biológico Ativo , Potenciais da Membrana , Processamento de Proteína Pós-TraducionalRESUMO
8-Hydroxy-2'-deoxyguanosine (8OH2'dG) is a principal stable marker of hydroxyl radical damage to DNA. It has been related to a wide variety of disorders and environmental insults, and has been proposed as a useful systematic marker of oxidative stress. Analytic procedures for 8OH2'dG in DNA digests are well established; however, routine measurement of free 8OH2'dG in other body fluids such as urine or plasma has been problematic. This has hindered its evaluation as a general clinical, therapeutic monitoring, or environmental assessment tool. Therefore, we developed a liquid chromatography electrochemical column-switching system based on the use of the unique purine selectivity of porous carbon columns that allows routine accurate measurement of 8OH2'dG in a variety of biologic matrices. This paper describes the rationale of the system design and the protocols developed for 8OH2'dG in urine, plasma, cerebrospinal fluid, tissue, DNA, saliva, sweat, kidney dialysis fluid, foods, feces, culture matrix, and microdialysates. Concentrations in both human and animal body fluids and tissues are reported. The system performance is discussed in the context of a 1-year evaluation of the methods applied to approximately 3600 samples, using internal quality control and external blind testing to determine long-term accuracy. The methods are reliable and accurate, and therefore should prove useful in assessing the role and utility of oxidative DNA damage in aging and human illness.
Assuntos
Cromatografia Líquida/métodos , Desoxiguanosina/análogos & derivados , 8-Hidroxi-2'-Desoxiguanosina , Esclerose Lateral Amiotrófica/urina , Animais , Biomarcadores/análise , Paralisia Cerebral/urina , Líquido Cefalorraquidiano/química , Cromatografia Líquida/normas , DNA/química , Dano ao DNA , Desoxiguanosina/análise , Desoxiguanosina/sangue , Desoxiguanosina/urina , Eletroquímica/instrumentação , Humanos , Estresse Oxidativo , Doença de Parkinson/urina , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Although the cause of amyotrophic lateral sclerosis (ALS) is unknown, substantial evidence indicates that oxidative toxicity is associated with neuronal death in this disease. We examined levels of a well-established marker of oxidative damage to DNA, 8-hydroxy-2'-deoxyguanosine (8OH2'dG) in plasma, urine, and cerebrospinal fluid (CSF) at a single time point from subjects with ALS, other neurological diseases, or no known disorders. We also measured the rate of change of 8OH2'dG levels in plasma and urine from ALS and in urine from control subjects over 9 months and examined the relationship to disease severity. In each fluid, 8OH2'dG levels were significantly elevated in the ALS group as compared to control subjects. In all subjects, the plasma and CSF 8OH2'dG levels increased with age, providing further evidence for a role of oxidative damage in normal aging. Plasma and urine 8OH2'dG levels increased significantly with time in the ALS group only. The rate of increase in urine 8OH2'dG levels with time was significantly correlated with disease severity. These findings are consistent with the hypothesis that oxidative pathology accompanies the neurodegenerative process in ALS and suggest that 8OH2'dG may provide a useful tool for monitoring therapeutic interventions in this disease.
Assuntos
Dano ao DNA , Desoxiguanosina/análogos & derivados , Desoxiguanosina/líquido cefalorraquidiano , Doença dos Neurônios Motores/líquido cefalorraquidiano , Doenças do Sistema Nervoso/líquido cefalorraquidiano , 8-Hidroxi-2'-Desoxiguanosina , Idade de Início , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/urina , Desoxiguanosina/sangue , Desoxiguanosina/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/urina , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/urina , Valores de Referência , Análise de RegressãoRESUMO
In this report we demonstrate that depletion of the major phospholipid phosphatidylethanolamine, a single non-bilayer forming phospholipid of Escherichia coli, significantly reduces the secretion efficiency of alkaline phosphatase in vivo. Secretion, however, is correlated with the content in membranes of cardiolipin, which in combination with selected divalent cations has a strong tendency to adopt a non-bilayer state indicating the possible involvement of lipid polymorphism in efficient protein secretion. Depletion of this zwitterionic phospholipid also inhibits expression of the protein controlled by the endogenous P(PHO) promoter but not the P(BAD) promoter, which is suggested to be due to the effect of unbalanced phospholipid composition on the orthophosphate signal transduction system (Pho regulon) through an effect on its membrane bound sensor.
Assuntos
Fosfatase Alcalina/metabolismo , Escherichia coli/metabolismo , Fosfatidiletanolaminas/metabolismo , Fosfatase Alcalina/genética , Sequência de Bases , Transporte Biológico Ativo , Cardiolipinas/metabolismo , Membrana Celular/metabolismo , Primers do DNA/genética , Escherichia coli/genética , Regulação Enzimológica da Expressão Gênica , Lipídeos de Membrana/metabolismo , Regiões Promotoras Genéticas , Transcrição GênicaRESUMO
Increased generation of reactive oxygen species may underlie the pathophysiology of Friedreich ataxia (FRDA). The authors measured concentrations of 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage, in urine and of dihydroxybenzoic acid (DHBA), a marker of hydroxyl radical attack, in plasma of 33 patients with FRDA. They found a 2.6-fold increase in normalized urinary 8OH2'dG but no change in plasma DHBA as compared with controls. Oral treatment with 5 mg/kg/day of the antioxidant idebenone for 8 weeks significantly decreased urinary 8OH2'dG concentrations, indicating that 8OH2'dG may be useful in monitoring therapeutic interventions in patients with FRDA.-1721
Assuntos
Desoxiguanosina/análogos & derivados , Desoxiguanosina/urina , Ataxia de Friedreich/urina , Estresse Oxidativo , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Ataxia de Friedreich/genética , HumanosRESUMO
Effects of new neuroleptics remoxipride (2.4 mg/kg, i.p.) and raclopride (1.2 mg/kg, i.p.) in comparison to metoclopramide (5 mg/kg, i.p.) on the extracellular levels of DA and its metabolites using microdialysis technique in freely moving rats were studied. The effects of these drugs as well as that of cis- and trans-carbidine (25 and 1 mg/kg, i.p., respectively), sulpride (50 mg/kg, i.p.) and haloperidol (1 mg/kg, i.p.) on the DA biosynthesis rate by accumulation of L-DOPA after inhibition of L-DOPA decarboxylase (NSD-1015 model) in rat striatum were also investigated. All the drugs studied increased significantly DA biosynthesis rate. The order of potency of drugs was: metoclopramide > haloperidol > raclopride > remoxipride > sulpride > cis-carbidine > trans-carbidine. In microdialysis study metoclopramide was shown to produce much greater increase in HVA and DOPAC and only modest rise in DA levels. Meanwhile remoxipride and raclopride were found to differ from the former drug being approximately equally effective in increasing both DA and its metabolite extracellular levels. It is suggested that typical and atypical neuroleptics may differentially affect dopamine release and synthesis in rat striatum.
Assuntos
Antipsicóticos/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Metoclopramida/farmacologia , Remoxiprida/farmacologia , Salicilamidas/farmacologia , Animais , Corpo Estriado/metabolismo , Dopamina/biossíntese , Masculino , Racloprida , Ratos , Ratos WistarRESUMO
Intracerebral microdialysis was used to monitor extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid and homovanillic acid in awake rats, after intraperitoneal administration of the cis- and trans-isomers (25 mg/kg and 1 mg/kg, respectively) of carbidine, the atypical neuroleptic drug, in comparison with sulpiride (50 mg/kg) and haloperidol (1 mg/kg). Trans-carbidine was found to be more potent than the cis-isomer in increasing the release of DA. In contrast to sulpiride and haloperidol, both isomers at the doses used, produced only a moderate elevation in the levels of the metabolites of DA. Transcarbidine seemed to be more potent as a neuroleptic drug, in comparison with the cis-isomer.
Assuntos
Antipsicóticos/farmacologia , Carbolinas/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Corpo Estriado/metabolismo , Diálise/métodos , Haloperidol/farmacologia , Ácido Homovanílico/metabolismo , Masculino , Ratos , Ratos Endogâmicos , Estereoisomerismo , Sulpirida/farmacologiaRESUMO
Necrotic and apoptotic cell death both play a role mediating tissue injury following brain trauma. Caspase-1 (interleukin-1beta converting enzyme) is activated and oligonucleosomal DNA fragmentation is detected in traumatized brain tissue. Reduction of tissue injury and free radical production following brain trauma was achieved in a transgenic mouse expressing a dominant negative inhibitor of caspase-1 in the brain. Neuroprotection was also conferred by pharmacological inhibition of caspase-1 by intracerebroventricular administration of the selective inhibitor of caspase-1, acetyl-Tyr-Val-Ala-Asp-chloromethyl-ketone or the non-selective caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. These results indicate that inhibition of caspase-1-like caspases reduces trauma-mediated brain tissue injury. In addition, we demonstrate an in vivo functional interaction between interleukin-1beta converting enyzme-like caspases and free radical production pathways, implicating free radical production as a downstream mediator of the caspase cell death cascade.
Assuntos
Clorometilcetonas de Aminoácidos/farmacologia , Lesões Encefálicas/patologia , Encéfalo/patologia , Inibidores de Caspase , Inibidores de Cisteína Proteinase/farmacologia , Radical Hidroxila/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Encéfalo/metabolismo , Lesões Encefálicas/genética , Caspase 1/fisiologia , Fragmentação do DNA , Interleucina-1/metabolismo , Camundongos , Camundongos Transgênicos/genéticaRESUMO
We demonstrate the use of magnetic resonance imaging (MRI) for detection of neurotransmitter stimulation using the dopamine transporter ligands amphetamine and CFT (2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane) as pharmacological challenges. We demonstrate that the unilateral loss of a hemodynamic response to either amphetamine or CFT challenge by unilateral 6-hydroxydopamine lesioning is restored by transplantation of fetal dopamine neurons in the striatum. The time course for the hemodynamic changes parallels the time courses for dopamine release, measured by prior microdialysis studies, and also for the rotational behavior in the unilaterally lesioned animals. Transplantation of the fetal cells results in hemodynamic time courses after CFT or amphetamine challenges at the graft site that are identical to those induced both before transplantation and on the intact contralateral side. The transplantation also results in complete behavioral recovery. The spatial extent of the dopaminergic recovery in the lesioned striatum is the same when measured using either PET of tracer levels of [11C]CFT binding or MRI. These results show great promise for the application of pharmacological MRI for application to studies of dopamine cell loss and potential recovery in Parkinson's disease.
Assuntos
Comportamento Animal/fisiologia , Transplante de Células/fisiologia , Dopamina/fisiologia , Neurônios/fisiologia , Anfetamina , Animais , Cocaína/análogos & derivados , Inibidores da Captação de Dopamina , Feminino , Imageamento por Ressonância Magnética , Microdiálise , Ratos , Ratos Sprague-Dawley , Degeneração Estriatonigral , Simpatectomia Química , Tomografia Computadorizada de EmissãoRESUMO
The excitability of cholinergic, glutamatergic and dopaminergic elements within the rat neostriatum was studied in both in vivo and in vitro preparations. In vivo, the microdialysis technique was used to measure the release of striatal acetylcholine and dopamine under basal and electrically evoked conditions. For comparison, acetylcholine, dopamine and glutamate release was assayed in media obtained from superfused rat striatal slices. Electrical stimulation was used to derive the strength-duration functions and their chronaxies of stimulated elements containing the three neurotransmitter types. The chonaxies for experiments in vitro and in vivo were similar: the chronaxy values for elements containing acetylcholine were the shortest, the values for glutamate were intermediate, and the values for those containing dopamine were the longest. Based on the chronaxy estimates, it is proposed that the elements containing acetylcholine are the large cholinergic interneurons of striatum, and the elements containing glutamate and dopamine are the terminals of corticostriatal and nigrostriatal neurons, respectively. These results indicate that electrical stimulation of neural elements surrounding a microdialysis probe can be an additional tool to examine the factors that regulate neurotransmitter release. Likewise, investigators can activate specific striatal elements by using pulse durations that coincide with their chronaxies.
Assuntos
Corpo Estriado/fisiologia , Neurônios/fisiologia , Acetilcolina/metabolismo , Animais , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Estimulação Elétrica , Eletrofisiologia , Ácido Glutâmico/metabolismo , Técnicas In Vitro , Masculino , Potenciais da Membrana/fisiologia , Microdiálise , Neurônios/metabolismo , Neurotransmissores/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
We examined effects of high doses of monosodium glutamate (MSG) on extracellular glutamate levels in rat striata, using in vivo microdialysis. Parenteral doses (0.5, 1.0 and 2.0, but not 0.25, g/kg, i.p.) caused dose- and time-dependent increases, peaking after 40 min (at 174 +/- 47%, 485 +/- 99% and 1021 +/- 301% of basal levels, respectively). In contrast, dietary MSG (1.49 +/- 0.10 g/kg/h) was ineffective.
Assuntos
Corpo Estriado/metabolismo , Ácido Glutâmico/metabolismo , Glutamato de Sódio/farmacologia , Administração Oral , Animais , Corpo Estriado/efeitos dos fármacos , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Masculino , Microdiálise/métodos , Ratos , Ratos Sprague-Dawley , Glutamato de Sódio/administração & dosagem , Fatores de TempoRESUMO
We used in vivo microdialysis to examine the acute effects of systemically administered nicotine (0.8-8.0 mg/kg, s.c.) on extracellular levels of serotonin (5-HT) in the frontal cortex of awake rats and animals anesthetized with chloralose/urethane. In anesthetized animals, 5-HT efflux was elevated during the initial 15 min after nicotine administration (2-8 mg/kg), but then returned to baseline values. All of the effective nicotine doses also lowered and then raised blood pressure in these animals. However, other drugs which raised (methoxamine, 0.07 mg/kg, i.v.) or lowered (mecamylamine, 5 mg/kg, i.p.) blood pressure without directly activating nicotinic receptors failed to alter 5-HT release. Moreover, pretreatment with a centrally active dose of mecamylamine, a known nicotinic antagonist, blocked the effects of nicotine (4 mg/kg) on 5-HT release. For studies on awake rats the perfusion fluid also contained fluoxetine, since basal 5-HT levels were barely detectable without this uptake blocker. In such animals, 1.6 mg/kg of nicotine significantly increased 5-HT release, an effect apparent in the initial 20 min after treatment and persisting for at least 2 h. These observations demonstrate that systemically administered nicotine increases frontocortical 5-HT release, that this effect is independent of the cardiovascular responses to the drug, and that it probably results from the activation of previously described nicotinic receptors on raphe neurons. The present findings are consistent with the hypothesis that the appetitive and mood disturbances associated with nicotine withdrawal may be mediated by diminished serotoninergic transmission.
Assuntos
Lobo Frontal/efeitos dos fármacos , Nicotina/farmacologia , Serotonina/metabolismo , Anestésicos , Animais , Pressão Sanguínea/efeitos dos fármacos , Lobo Frontal/metabolismo , Masculino , Mecamilamina/farmacologia , Metoxamina/farmacologia , Microdiálise , Ratos , Ratos Sprague-DawleyRESUMO
We examined the effects of systemic or oral ad libitum monosodium glutamate (MSG) administration on glutamate levels in plasma, and on glutamate release from the arcuate nucleus of the hypothalamus (estimated using brain microdialysis). Systemic MSG administration (0.25, 0.5, 1 or 2 g/kg, i.p.) to adult rats caused dose-dependent increases in glutamate levels within arcuate nucleus dialysates. These levels increased during the initial 20 min after systemic MSG administration, and peaked during the second 20-min interval (maximally to 116 +/- 7%, 146 +/- 15%, 790 +/- 191% and 1230 +/- 676% of basal values, respectively). Plasma glutamate levels, measured simultaneously, were increased maximally during the initial 20 min after MSG administration. These increases were 10-, 13-, 76- and 163-fold after doses of 0.25, 0.5, 1 and 2 g/kg, i.p., respectively. In feeding experiments, consumption of 2.3 g/kg of MSG by previously-trained rats during an 1-h period increased plasma glutamate levels to 352 +/- 61% of basal values 140 min after the start of the feeding period. No changes were observed in glutamate levels of arcuate nucleus dialysates. These findings may explain why ad libitum dietary consumption of MSG apparently lacks neurotoxic potential.
Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Ácido Glutâmico/metabolismo , Glutamato de Sódio/farmacologia , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Dieta , Relação Dose-Resposta a Droga , Ácido Glutâmico/sangue , Injeções Intraperitoneais , Cinética , Masculino , Ratos , Ratos Sprague-Dawley , Valores de Referência , Glutamato de Sódio/administração & dosagemRESUMO
The effects of buspirone (5 and 10 mg/kg i.p.), 8-OH-DPAT (0.25 mg/kg) and raclopride (2.5 mg/kg) on the EEG power spectra of the sensorimotor cortex were studied in freely moving rats. Buspirone (5 mg/kg) and 8-OH-DPAT produced selective slowing of the theta-activity. Buspirone (10 mg/kg) produced slowing of the theta-activity and increased the power of the alpha-band (9-11 Hz). Raclopride alone did not influence EEG power spectra. Simultaneous injection of 8-OH-DPAT and raclopride produced marked slowing of the theta-activity and increased the power of the alpha-band. The role of 5 HT1A and D2 dopamine receptors in buspirone effects on cortical electrical activity in rats was discussed.