RESUMO
AIM: The aim of this study was to examine the role of IL-33/ST2 pathway in a pathogenesis of acute inflammation and its effects on tissue damage, antioxidative capacity, magnesium concentration and cytokine profile in acutely inflamed tissue. MATERIAL AND METHODS: Male mice were randomly divided in four groups: wild-type control group (WT-C), ST2 knockout control group (KO-C), wild-type inflammatory group (WT-I), and ST2 knockout inflammatory group (KO-I). Acute inflammation was induced in WT-I and KO-I by intramuscular injection of turpentine oil, while mice in WT-C and KO-C were treated with saline. After 12h, animals were euthanized, and blood was collected for determination of creatine kinase (CK) and aspartate transaminase (AST) activity. The treated tissue was used for histopathological analysis, determination of volume density of inflammatory infiltrate (Vdii) and necrotic fiber (Vdnf), gene expression of interleukin (IL)-33, ST2, tumor necrosis factor alpha (TNF-alpha), IL-6, IL-12p35, and transforming growth factor beta (TGF-beta), concentration of magnesium (Mg), copper (Cu), selenium (Se), manganese (Mn) and reduced glutathione (GSH), and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity. RESULTS: Presence of inflammatory infiltration and necrosis in the treated tissue was histopathologically confirmed in WT-I and KO-I. Vdii was significantly higher in WT-I when compared to KO-I, whereas Vdnf did not significantly differ between WT-I and KO-I. CK and AST significantly increased in both inflammatory groups when compared to corresponding control groups. However, the values of CK and AST were significantly higher in WT-I than in KO-I. Mg in the treated tissue was significantly lower in WT-I in comparison to WT-C and KO-I, while there was no significant difference between KO-C and KO-I. There was no significant difference in Cu, Se, and Mn in the treated tissue between WT-C, KO-C, WT-I and KO-I. Gene expression of IL-33 in the treated tissue increased in both inflammatory groups when compared to the corresponding control groups, but it was significantly higher in KO-I than in WT-I. Gene expression of ST2 in the treated tissue was significantly higher in WT-I than in WT-C. Gene expression of TNF-alpha, IL-6, and IL-12p35 in the treated tissue was significantly higher in WT-I and KO-I than in the corresponding control groups, and IL-6 was significantly higher in KO-C than in WT-C. TGF-beta gene expression in the treated tissue was significantly higher in KO-I when compared to WT-I, while there was no difference between WT-C and KO-C. SOD activity decreased at the site of acute inflammation in both inflammatory groups, while the GPx activity increased. GSH in the treated tissue was significantly higher in KO-I than in KO-C or WT-I. CONCLUSION: The results of our study have indicated, to our knowledge for the first time, that IL-33/ST2 pathway plays a role in enhancing inflammation and tissue damage at the site of acute inflammation by affecting the concentration of magnesium and GSH, important for antioxidative capacity, as well as gene expression of anti-inflammatory cytokine TGF-beta.
Assuntos
Antioxidantes/metabolismo , Inflamação/patologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Magnésio/metabolismo , Músculos/patologia , Animais , Aspartato Aminotransferases/sangue , Cobre/metabolismo , Creatina Quinase/metabolismo , Regulação da Expressão Gênica , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Inflamação/sangue , Inflamação/enzimologia , Inflamação/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/genética , Masculino , Manganês/metabolismo , Camundongos Endogâmicos BALB C , Músculos/efeitos dos fármacos , Músculos/metabolismo , Selênio/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta/farmacologiaRESUMO
BACKGROUND: The variations in proinflamatory cytokine levels have been associated with schizophrenia (SCH), duration of illness, psychopathology and treatment. The aim of the study was to investigate serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in schizophrenic patients during exacerbation and remission, and its association with course of illness and therapy. SUBJECTS AND METHODS: We measured serum levels of IL-6 and TNF-α in 43 schizophrenic patients in exacerbation and remission and compared them to 29 healthy controls, matched by sex, age, body mass index (BMI) and smoking habits. The severity of psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). RESULTS: There was no difference in levels of IL-6 and TNF-α in exacerbation compared to remission in schizophrenic patients. IL-6 was higher and TNF-α was lower in schizophrenic patients in both exacerbation and remission in comparison with healthy controls. TNF-α in exacerbation was in negative correlation with IL-6 in remission. No statistical significance was found between levels of cytokines and sex, age, BMI, smoking habits, antipsychotic medication, duration of treatment and duration of illness. IL-6 levels were in positive correlation with the age of onset and the duration of untreated psychosis. In schizophrenic patients on adjunctive treatment with mood stabilizers, TNF-α levels increased in remission. CONCLUSION: Our results suggest that the connection between schizophrenia, cytokines and medication is multifaceted, and not necessarily linear. Adjunct mood stabilizers not only ameliorate psychopathology, but might convey immunomodulatory effects as well. Further longitudinal studies could elucidate potential beneficial effect of combined therapy in treatment of SCH.
Assuntos
Progressão da Doença , Interleucina-6/sangue , Esquizofrenia/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Antimaníacos/uso terapêutico , Antipsicóticos/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Quimioterapia de Indução , Inflamação/sangue , Interleucina-6/imunologia , Masculino , Esquizofrenia/tratamento farmacológico , Esquizofrenia/imunologia , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Colorectal cancer is one of the leading causes of cancer related death in developed countries. One of the reasons is the absence of tumor specific diagnostic and prognostic markers. The aim of this study was to examine the correlation of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) expressions in serum and clinicopathological features of the colorectal adenocarcinoma. Another aim was to examine expression of MMP-9 in the tissue of the colorectal carcinoma in MMP-9 serum positive patients. In addition, we tried to establish the correlation between preoperative levels of serum markers (CEA and CA 19-9) and presence of MMP-2 or MMP-9. The study was performed on 32 patients with colorectal adenocarcinoma who underwent surgery and 11 patients in a control group who were operated for benign diseases. The samples were analyzed by SDS-PAGE to determine the molecular mass and SDS-PAGE zymography to determine levels of MMP-2 and MMP-9. Expression of MMP-9 was determined immunohistochemically in the tissue of the colorectal carcinoma of MMP-9 serum positive patients. MMP-2 and MMP-9 levels were increased in the serum of the patients with colorectal cancer compared to the control group. There was significant correlation in MMPs levels among the patients with tumor stage I and II and the patients with tumor stage III and IV. Obtained results did not demonstrate correlation between levels of CEA, CA 19-9 and presence of MMP-2 or MMP-9. MMP-9 expression was positive in 85% of MMP-9 serum positive patients with colorectal carcinoma. The overexpression of MMP-2 and MMP-9 strongly suggests its association with colorectal adenocarcinoma. Detection of MMP-2 and MMP-9 in serum might be useful for identification of patients with higher risk for colorectal cancer recurrence.
Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/diagnóstico , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Período Pré-Operatório , Adenocarcinoma/sangue , Adenocarcinoma/enzimologia , Antígeno CA-19-9/sangue , Antígeno Carcinoembrionário/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/enzimologia , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , PrognósticoRESUMO
Olive leaf extract (OLE) possesses, among other, antioxidative properties, but whether it influences gastroprotection against stress-induced gastric lesions remains unknown. In this study we investigated the protective effect of OLE, a natural antioxidant, on gastric mucosal damage induced by cold restraint stress (CRS) in rats. Three different doses of commercial OLE EFLA((R)) 943 were applied intragastrically (i.g.) 30 min prior to stress induction. Macroscopic gastric lesions were evaluated and ulcer index (UI) was calculated. Histological evidence of gastric mucosal lesions was also obtained. Concentration of malondialdehyde (MDA) as an index of lipid peroxidation, and catalase (CAT) and superoxide dismutase (SOD) activities were determined in gastric mucosa. The effects of applied OLE on gastric mucosal lesions, lipid peroxidation and antioxidative enzymes activity were compared with effects of i.g. pretreatment of reference drug, ranitidine. CRS caused severe gastric lesions in all non-pretreated animals, and this finding was confirmed histologicaly. Pretreatment with OLE (40, 80 and 120 mg.kg(-1)), as well as with ranitidine (50 mg.kg(-1)), significantly (p < 0.001) attenuated stress-induced gastric lesions. Treatment with 80 mg.kg(-1) of OLE was the most effective in prevention of rise in gastric MDA level and decrease in CAT and SOD activity. The results obtained indicate that OLE possesses gastroprotective activity against CRS-induced gastric lesions in rats, possibly related to its antioxidative properties.
Assuntos
Temperatura Baixa , Olea/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Úlcera Gástrica/etiologia , Úlcera Gástrica/prevenção & controle , Estresse Psicológico/complicações , Animais , Antioxidantes/metabolismo , Enzimas/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/enzimologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Restrição Física , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , SuspensõesRESUMO
High levels of homocysteine (Hcy) were suggested to contribute to the pathogenesis of schizophrenia. Recent investigations have shown that treatment with folic acid, vitamin B-12 and pyridoxine are effective in reducing Hcy levels while concomitantly reducing the score of positive and negative symptoms in schizophrenic patients. In addition to the availability of nutrients (mainly folate, vitamins B6 and B12), plasma Hcy concentrations are dependent on complex metabolic regulation that could be disrupted in schizophrenia. This study was designed to test the influence of disease activity on plasma Hcy levels. Plasma Hcy concentrations were measured in male chronic schizophrenic patients with a predominantly positive (SCH (+)) or predominantly negative (SCH (-)) syndrome in schizophrenia immediately upon admission to the hospital (exacerbation phase) and one month later (remission phase). During this period patients received antipsychotic medications without vitamin therapy. The effects of age, duration of illness, folate and B12 concentrations, as well as smoking and coffee consumption habits on the observed changes were evaluated. Age- and sex-matched subjects were included in the control group. In the control group plasma Hcy concentration was 8.75+/-1.84 micromol/L. In the exacerbation phase plasma Hcy concentrations were significantly increased both in SCH (+) (14.91+/-6.19 micromol/L) and SCH (-) groups (12.8+/-3.27 micromol/L). There was no difference in plasma Hcy concentrations between SCH (+) and SCH (-) patients. Serum folate and B12 concentrations were not significantly different in any of the investigated groups of subjects. The plasma Hcy concentrations could not be correlated with age, duration of illness, the score of positive symptoms or the concentration of folate and vitamin B12. A positive correlation was found between plasma Hcy level and score of negative symptoms in both groups of patients. No correlation was found between smoking or coffee consumption habits and plasma Hcy concentrations. All patients exhibited decreased plasma Hcy levels in the remission phase of the illness, with a mean decrease of 2.68+/-1.57 micromol/L. Folate and B12 levels did not differ in the exacerbation and remission phases of the illness. The significant decrease of plasma Hcy levels, without changes in folate and vitamin B12 concentrations in the remission phase of schizophrenia, could indicate an influence of a pathogenetic process involved in schizophrenia on Hcy metabolism.
Assuntos
Homocisteína/sangue , Esquizofrenia/sangue , Esquizofrenia/fisiopatologia , Adulto , Análise de Variância , Antipsicóticos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estatística como Assunto , Adulto JovemRESUMO
Phencyclidine (PCP), a dissociative anaesthetic, acts as a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. PCP is a psychostimulant capable of producing both positive and negative symptoms of schizophrenia, including cognitive dysfunction in normal humans. Perinatal phencyclidine administration to rats has been widely accepted as an animal model of schizophrenia. It has been known for a long time that schizophrenia patients may develop various thermoregulatory disturbances. The aim of this study was to assess the acute effects of phencyclidine administration on the temperature of newborn rats, the long-term effects on the baseline temperature of perinatal phencyclidine administration and the effects of a PCP challenge on the temperature of adult perinatally treated rats. The animals were treated on the 2nd, 6th, 9th and 12th postnatal (PN) days with either phencyclidine (10 mg/kg) or saline. The interscapular skin temperature was measured during the first 40 postnatal days and subsequently the colonic temperature until PN day 62. The immediate effect of phencyclidine administration to pups was a significant decrease of the body temperature, while the application of PCP to adult rats perinatally treated with either saline or PCP caused a significant increase of the baseline temperature. Perinatal phencyclidine administration to rat pups produced a long lasting effect on the baseline temperature. It can be concluded that the nature of the response to acute phencyclidine administration differs between newborn and adult rats. Further experiments are necessary in order to clarify the role of specific neurotransmitter systems in the changes of temperature regulation provoked by phencyclidine administration.
Assuntos
Temperatura Corporal/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Fenciclidina/administração & dosagem , Esquizofrenia/induzido quimicamente , Esquizofrenia/fisiopatologia , Fatores Etários , Animais , Animais Recém-Nascidos , Regulação da Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Gravidez , Ratos , Ratos WistarRESUMO
Ageing affects various physiological and metabolic processes in a body and a progressive accumulation of oxidative damage stands out as often used explanation. One of the most powerful scavenger of reactive oxygen species (ROS) in all organs is melatonin. A majority of melatonin supplied to the body via blood originates from the pineal gland. However, we have been interested in a locally produced melatonin. We have used 2.5- and 36-months-old Wistar rats. Tissues were collected and gene expression of AA-NAT and ASMT, the two key enzymes in a synthesis of melatonin, was determined in brain, liver, kidney, heart, skin, and intestine. Since melatonin can influence antioxidant enzymes, the activity of superoxide dismutase (SOD) and catalase (CAT), and the level of GSH were measured in liver. In addition, Copper (Cu), Zinc (Zn), and Manganese (Mn) were also determined in liver since these microelements might affect the activity of antioxidant enzymes. The expression of AA-NAT and ASMT was increased in liver and skin of old animals. A positive correlation in AA-NAT and ASMT expression was observed in liver, intestine and kidney. Moreover, the activity of CAT enzyme in liver was increased while SOD activity was decreased. SOD and CAT were probably affected by the observed decreased amount of Cu, Zn, and Mn in liver of old animals. In our model, extrapineal melatonin pathway in ageing consisted of complex interplay of locally produced melatonin, activities of SOD and CAT, and adequate presence of Cu, Zn and Mn microelements in order to defend organs against oxidative damage.
Assuntos
Envelhecimento/metabolismo , Fígado/metabolismo , Melatonina/metabolismo , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Cobre/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Zinco/metabolismoRESUMO
Decreased blood flow in the brain leads to a rapid increase in reactive oxygen species (ROS). NADPH oxidase (NOX) is an enzyme family that has the physiological function to produce ROS. NOX2 and NOX4 overexpression is associated with aggravated ischemic injury, while NOX2/4-deficient mice had reduced stroke size. Dysregulation of matrix metalloproteinases (MMPs) contributes to tissue damage. The active form of vitamin D3 expresses neuroprotective, immunomodulatory, and anti-inflammatory effects in the CNS. The present study examines the effects of the vitamin D3 pretreatment on the oxidative stress parameters and the expression of NOX subunits, MMP9, microglial marker Iba1, and vitamin D receptor (VDR), in the cortex and hippocampus of Mongolian gerbils subjected to ten minutes of global cerebral ischemia, followed by 24 hours of reperfusion. The ischemia/reperfusion procedure has induced oxidative stress, changes in the expression of NOX2 subunits and MMP9 in the brain, and increased MMP9 activity in the serum of experimental animals. Pretreatment with vitamin D3 was especially effective on NOX2 subunits, MMP9, and the level of malondialdehyde and superoxide anion. These results outline the significance of the NOX and MMP9 investigation in brain ischemia and the importance of adequate vitamin D supplementation in ameliorating the injury caused by I/R.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/enzimologia , Colecalciferol/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , NADPH Oxidases/metabolismo , Animais , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Gerbillinae , MasculinoRESUMO
Maternal deprivation (MD) causes perinatal stress, with subsequent behavioral changes which resemble the symptoms of schizophrenia. The NADPH oxidase is one of the major generators of reactive oxygen species, known to play a role in stress response in different tissues. The aim of this study was to elucidate the long-term effects of MD on the expression of NADPH oxidase subunits (gp91phox, p22phox, p67phox, p47phox, and p40phox). Activities of cytochrome C oxidase and respiratory chain Complex I, as well as the oxidative stress parameters using appropriate spectrophotometric techniques were analyzed. Nine-day-old Wistar rats were exposed to a 24 h maternal deprivation and sacrificed at young adult age. The structures affected by perinatal stress, cortex, hippocampus, thalamus, and caudate nuclei were investigated. The most prominent findings were increased expressions of gp91phox in the cortex and hippocampus, increased expression of p22phox and p40phox, and decreased expression of gp91phox, p22phox, and p47phox in the caudate nuclei. Complex I activity was increased in all structures except cortex. Content of reduced glutathione was decreased in all sections while region-specific changes of other oxidative stress parameters were found. Our results indicate the presence of long-term redox alterations in MD rats.
Assuntos
Encéfalo/metabolismo , NADPH Oxidases/metabolismo , Animais , Núcleo Caudado/metabolismo , Córtex Cerebelar/metabolismo , Regulação para Baixo , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hipocampo/metabolismo , Privação Materna , Glicoproteínas de Membrana/metabolismo , NADPH Oxidase 2 , Oxirredução , Estresse Oxidativo , Fosfoproteínas/metabolismo , Ratos , Ratos Wistar , Regulação para CimaRESUMO
Phencyclidine (PCP) acts as a non-competitive antagonist of glutamatergic N-methyl-d-aspartate receptor. Its perinatal administration to rats causes pathophysiological changes that mimick some pathological features of schizophrenia (SCH). Numerous data indicate that abnormalities in mitochondrial structure and function could be associated with the development of SCH. Mitochondrial dysfunction could result in the activation of apoptosis and/or autophagy. The aim of this study was to assess immediate and long-term effects of perinatal PCP administration and acute restraint stress on the activity of respiratory chain enzymes, expression of apoptosis and autophagy markers and ultrastructural changes in the cortex and hippocampus of the rat brain. Six groups of rats were subcutaneously treated on 2nd, 6th, 9th and 12th postnatal days (P), with either PCP (10mg/kg) or saline (0.9% NaCl). One NaCl and one PCP group were sacrificed on P13, while other two NaCl and PCP groups were sacrificed on P70. The remaining two NaCl and PCP groups were subjected to 1h restraint stress prior sacrifice on P70. Activities of respiratory chain enzymes were assessed spectrophotometrically. Expression of caspase 3 and AIF as markers of apoptosis and Beclin 1, p62 and LC3, as autophagy markers, was assessed by Western blot. Morphological changes of cortical and hippocampal ultrastructure were determined by transmission electron microscopy. Immediate effects of perinatal PCP administration at P13 were increased activities of complex I in the hippocampus and cytochrome c oxidase (COX) in the cortex and hippocampus implying mitochondrial dysfunction. These changes were followed by increased expression of apoptotic markers. However the measurement of autophagy markers at this time point has revealed decrease of this process in cortex and the absence of changes in hippocampus. At P70 the activity of complex I was unchanged while COX activity was significantly decreased in cortex and increased in the hippocampus. Expressions of apoptotic markers were still significantly higher in PCP perinatally treated rats in all investigated structures, but the changes of autophagy markers have indicated increased level of autophagy also in both structures. Restraint stress on P70 has caused increase of COX activity both in NaCl and PCP perinatally treated rats, but this increase was lower in PCP group. Also, restraint stress resulted in decrease of apoptotic and increase of autophagy processes especially in the hippocampus of PCP perinatally treated group. The presence of apoptosis and autophagy in the brain was confirmed by transmission electron microscopy. In this study we have demonstrated for the first time the presence of autophagy in PCP model of SCH. Also, we have shown increased sensitivity of PCP perinatally treated rats to restraint stress, manifested in alterations of apoptotic and autophagy markers. The future studies are necessary to elucidate the role of mitochondria in the pathophysiology of SCH and putative significance for development of novel therapeutic strategies.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fenciclidina/farmacologia , Restrição Física , Animais , Fator de Indução de Apoptose/metabolismo , Caspase 3/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/ultraestrutura , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Ratos , Ratos WistarRESUMO
In this study, the activity of total superoxide dismutase was investigated in brains of adult Mongolian gerbils (Meriones unguiculatus) treated with aluminum. AlCl3x6H20, was given "per os" in the amount of 3.7 g/kg body weight. Animals were killed 24, 48, 72 and 96 hours after the treatment and SOD activity was measured in crude mitochondrial fractions of cortex, thalamus and hippocampus. The SOD activity was significantly elevated in all investigated brain regions 24 hours after aluminum administration. The most prominent increases (up to 200% of values in control animals) were detected in thalamus and hippocampus, whereas the activity was 165% of control value in the cortex. The SOD activity returned to control values in all regions investigated forty-eight hours after poisoning. A slight secondary increases in SOD activity were observed at 72 hours, reaching 171%, 148%, and 166% of control values in the thalamus, hippocampus and cortex, respectively, 96 hours after AlCl3x6H20 administration. We conclude that Al administration causes a biphasic stimulation of SOD activity in various brain regions over 96 hours, providing evidence that oxidative stress is involved in aluminum toxicity to the brain.
Assuntos
Alumínio/intoxicação , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Superóxido Dismutase/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Gerbillinae , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/enzimologia , Fatores de TempoRESUMO
Previous studies have shown decreased erythrocyte membrane (EM) Na,K-ATPase activity in chronic patients suffering from schizophrenia (SCH). There are no data about changes at the onset of psychosis and enzyme kinetics. Increased lipid peroxidation could be responsible for alterations in Na,K-ATPase activity. Substrate kinetics pattern of EM Na,K-ATPase and levels of lipid peroxides in plasma and erythrocytes were measured in (1) patients with first episode of psychosis (n=20) before medication and after the first 3 weeks of treatment, (2) chronic medicated schizophrenic patients (n=52) in the exacerbation phase, and (3) age- and sex-matched control subjects (n=30). All patients were assigned to groups with predominantly positive or predominantly negative symptoms on the basis of their scores on Positive and Negative Syndrome Scale (PANSS). In first-episode patients with predominantly negative symptoms before treatment, uncompetitive inhibition of Na,K-ATPase was noticed. The first-episode patients with predominantly positive symptoms had increased enzyme catalytic activity. After 3 weeks of treatment, activities were normalized in both groups. Among chronic patients, uncompetitive inhibition was found only in patients with predominantly negative symptoms. Plasma lipid peroxides (thiobarbituric acid-reactive substances [TBARS]) were elevated in both groups of patients with first episode of psychosis. Despite the presence of peroxidative injury indicative for the loss of membrane phospholipid essential fatty acids, the activities of Na,K-ATPase differ between SCH (+) and SCH (-) patients.
Assuntos
Membrana Eritrocítica/enzimologia , Peróxidos Lipídicos/sangue , Esquizofrenia/sangue , Esquizofrenia/enzimologia , ATPase Trocadora de Sódio-Potássio/sangue , Adolescente , Adulto , Análise de Variância , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/tratamento farmacológico , Especificidade por Substrato/efeitos dos fármacos , Especificidade por Substrato/fisiologiaRESUMO
RATIONALE: Perinatal phencyclidine (PCP) administration in rat blocks the N-methyl D-aspartate receptor (NMDAR) and causes symptoms reminiscent of schizophrenia in human. A growing body of evidence suggests that alterations in γ-aminobutyric acid (GABA) interneuron neurotransmission may be associated with schizophrenia. Neuregulin-1 (NRG-1) is a trophic factor important for neurodevelopment, synaptic plasticity, and wiring of GABA circuits. OBJECTIVES: The aim of this study was to determine the long-term effects of perinatal PCP administration on the projection and local circuit neurons and NRG-1 expression in the cortex and hippocampus. METHODS: Rats were treated on postnatal day 2 (P2), P6, P9, and P12 with either PCP (10 mg/kg) or saline. Morphological studies and determination of NRG-1 expression were performed at P70. RESULTS: We demonstrate reduced densities of principal neurons in the CA3 and dentate gyrus (DG) subregions of the hippocampus and a reduction of major interneuronal populations in all cortical and hippocampal regions studied in PCP-treated rats compared with controls. For the first time, we show the reduced density of reelin- and somatostatin-positive cells in the cortex and hippocampus of animals perinatally treated with PCP. Furthermore, an increase in the numbers of perisomatic inhibitory terminals around the principal cells was observed in the motor cortex and DG. We also show that perinatal PCP administration leads to an increased NRG-1 expression in the cortex and hippocampus. CONCLUSION: Taken together, our findings demonstrate that perinatal PCP administration increases NRG-1 expression and reduces the number of projecting and local circuit neurons, revealing complex consequences of NMDAR blockade.
Assuntos
Antagonistas de Aminoácidos Excitatórios/toxicidade , Neuregulina-1/genética , Fenciclidina/toxicidade , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Fenciclidina/administração & dosagem , Gravidez , Ratos , Proteína Reelina , Fatores de TempoRESUMO
Several studies suggest that aluminum (Al) intake might increase an individual's risk of developing Alzheimer disease. The dynamic of changes in acetylcholinesterase (AChE), cytochrome c oxidase (COX), Complex I, superoxide dismutase (SOD) and catalase (CAT) activities, and the lipid peroxide (MDA), superoxide anion (O2(-)) and thiol (SH) group levels in gerbil's brain after aluminum ingestion were analyzed. Gerbils that orally received aluminum chloride (LD25 or LD50) were sacrificed 2, 6 or 24 h later. Another group was subacutely treated (21 days; LD10). Controls received saline. Biochemical parameters were measured in cortex, hippocampus, thalamus and nucleus caudatus. Two hours after acute Al exposure AChE activity and SH group content were decreased and MDA and O2(-) levels were elevated in all investigated brain structures. The changes of COX and CAT were structure specific. SOD was increased after 6 h. Changes of investigated parameters were also seen after subacute Al treatment. These results might suggest the presence of additional source of free radicals in early phase of Al poisoning.
Assuntos
Compostos de Alumínio/toxicidade , Encefalopatias/induzido quimicamente , Encefalopatias/metabolismo , Cloretos/toxicidade , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Cloreto de Alumínio , Animais , Química Encefálica/efeitos dos fármacos , Catalase/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Gerbillinae , Dose Letal Mediana , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismo , Superóxidos/metabolismoRESUMO
BACKGROUND AND PURPOSE: Growing scientific evidence indicates that there is a correlation between depression and alternations in the immune system. The main aim of the study was to investigate serum levels of Interleukin-6 (IL-6) and Tumour Necrosis Factor-alpha (TNF-α) in melancholic and atypical depressive patients during acute exacerbations of illness, compared to healthy subjects. The secondary aim was to explore a possible association between cytokine levels and clinical characteristics, as well as total duration of prior antidepressant treatment. METHOD: We measured serum levels of IL-6 and TNF-α in 47 patients suffering from major depressive disorder (MDD) (29 melancholic and 18 atypical) in exacerbation of illness, compared to 39 healthy controls, matched by sex, body mass index (BMI) and smoking habits. Serum levels of IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). The severity of psychopathology was assessed using the Hamilton Depression Rating Scale (HDRS). RESULTS: IL-6 was significantly elevated in melancholic depressive patients (MDD-M) compared to healthy controls, while no difference was found between the patients with atypical depression (MDD-A) and the healthy group. Lower TNF-α serum level was found both in melancholic and in patients with atypical depression, compared with healthy subjects. We detected a positive correlation between cytokine levels in atypical, but not in melancholic subjects. Sex, age, smoking habits and BMI were not associated to cytokine levels in neither group. Clinical parameters (duration of illness, current episode, age of onset) were related to cytokine levels in atypical depression, while the duration of lifetime exposure to antidepressant treatment correlated to IL-6 serum levels in both melancholic and atypical depression. CONCLUSION: Our results suggest that the difference in pro-inflammatory cytokine levels could reflect a biological difference between melancholic and atypical depression. A positive correlation between the cytokines (TNF-α and IL-6) observed in depressive patients with atypical features, might be influenced by chronic course of illness, while IL-6 elevation could represent a state indicator for acute exacerbation, especially in melancholic patients. Total duration of antidepressant treatment could be a relevant factor influencing the immune status of patients who suffer either from melancholic or atypical depression.
Assuntos
Citocinas/sangue , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/terapia , Adulto , Idade de Início , Análise de Variância , Antidepressivos/uso terapêutico , Estudos Transversais , Transtorno Depressivo Maior/psicologia , Progressão da Doença , Escolaridade , Feminino , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Fumar/efeitos adversos , Fumar/psicologia , Fatores Socioeconômicos , Ideação Suicida , Fator de Necrose Tumoral alfa/sangueRESUMO
Perinatal phencyclidine (PCP) administration to rats represents one of the actual animal models of schizophrenia. Numerous data suggest redox dysregulation in this disease. We have previously demonstrated decreased content of the reduced glutathione (GSH) and complex disbalance of antioxidant enzymes in the brain of rats perinatally treated with PCP. The aim of this study was to elucidate whether chronic risperidone treatment can reverse these changes. The Wistar rats were perinatally treated with either PCP (10mg/kg; PCP, two groups) or saline (0.9% NaCl, two groups). At postnatal day (PN) 35, two groups of rats one NaCl and one PCP have started to receive risperidone in drinking water for nine weeks (NaCl-RSP and PCP-RSP groups). Animals were sacrificed on PN100 and the levels of GSH, the activities of γ-glutamate cysteine ligase (GCL), glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD), as well as, the concentration of lipid peroxides were determined in the different brain structures. Risperidone restored decreased GSH levels, as well as decreased γ-GCL activity in cortex and hippocampus of animals perinatally treated with PCP. Alterations in GPx and GR activities caused by perinatal PCP treatment were also reversed by risperidone in most investigated brain structures. Furthermore, chronic risperidone treatment caused the decrease in SOD activity both in control and in PCP perinatally treated groups. Increased levels of lipid peroxides noticed in hippocampus and thalamus were reversed after chronic risperidone treatment. The results of the present study demonstrate that risperidone treatment restores GSH levels and to great measure reverses antioxidant defense alterations in the brain of perinatally PCP treated rats. Further studies are necessary in order to clarify the significance of risperidone influence on oxidative stress parameters in schizophrenia.
Assuntos
Antioxidantes/metabolismo , Encéfalo/metabolismo , Glutationa/metabolismo , Fenciclidina/antagonistas & inibidores , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Risperidona/farmacologia , Esquizofrenia/metabolismo , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Glutamato-Cisteína Ligase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Ratos , Ratos Wistar , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológicoRESUMO
BACKGROUND AND AIM: Free radicals are implicated in the aetiology of gastrointestinal disorders such as gastric ulcer, colorectal cancer and inflammatory bowel disease. Strawberries are common and important fruit due to their high content of essential nutrient and beneficial phytochemicals which seem to have relevant biological activity on human health. In the present study we investigated the antioxidant and protective effects of three strawberry extracts against ethanol-induced gastric mucosa damage in an experimental in vivo model and to test whether strawberry extracts affect antioxidant enzyme activities in gastric mucosa. METHODS/PRINCIPAL FINDINGS: Strawberry extracts were obtained from Adria, Sveva and Alba cultivars. Total antioxidant capacity and radical scavenging capacity were performed by TEAC, ORAC and electron paramagnetic resonance assays. Identification and quantification of anthocyanins was carried out by HPLC-DAD-MS analyses. Different groups of animals received 40 mg/day/kg body weight of strawberry crude extracts for 10 days. Gastric damage was induced by ethanol. The ulcer index was calculated together with the determination of catalase and SOD activities and MDA contents. Strawberry extracts are rich in anthocyanins and present important antioxidant capacity. Ethanol caused severe gastric damage and strawberry consumption protected against its deleterious role. Antioxidant enzyme activities increased significantly after strawberry extract intake and a concomitantly decrease in gastric lipid peroxidation was found. A significant correlation between total anthocyanin content and percent of inhibition of ulcer index was also found. CONCLUSIONS: Strawberry extracts prevented exogenous ethanol-induced damage to rats' gastric mucosa. These effects seem to be associated with the antioxidant activity and phenolic content in the extract as well as with the capacity of promoting the action of antioxidant enzymes. A diet rich in strawberries might exert a beneficial effect in the prevention of gastric diseases related to generation of reactive oxygen species.
Assuntos
Antioxidantes/metabolismo , Etanol/efeitos adversos , Fragaria/química , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/lesões , Malondialdeído/metabolismo , Polifenóis/farmacologia , Adulto , Animais , Catalase/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Ativação Enzimática/efeitos dos fármacos , Mucosa Gástrica/enzimologia , Mucosa Gástrica/patologia , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Pigmentos Biológicos/análise , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
Perinatal phencyclidine (PCP) administration to rodents represents one of the more compelling animal models of schizophrenia. There is evidence that decreased glutathione (GSH) levels and oxidative stress mediated through free radicals in the central nervous system are involved in the pathophysiology of this disease. Limited data are available on the role of free radicals in neurotoxicity induced by NMDA-receptor antagonists. The aim of this study was to elucidate the long-term effects of perinatal phencyclidine administration on superoxide dismutase (SOD), catalase (CAT), gamma-glutamyl cisteine ligase (gamma-GCL), glutathione peroxidase (GPx), glutathione reductase (GR) and levels of lipid peroxides as well as GSH content. The Wistar rats were treated on the 2nd, 6th, 9th and 12th postnatal (PN) days with either phencyclidine (10mg/kg) or saline and sacrificed on PN70. The activities of antioxidant enzymes and level of lipid peroxides and GSH were determined in dorsolateral frontal cortex (dlFC), hippocampus, thalamus and caudate nucleus. Expression of SOD1 and SOD2 was determined by immunoblot. Region-specific changes of the measured parameters were observed. Decreased content of reduced GSH and altered activities of GR, GPx and SOD were determined in dlFC. In hippocampus, reduced GSH content and decreased activities of GPx and GR were accompanied with increased activity of gamma-GCL and increased level of lipid peroxides. gamma-GCL and GSH content were also decreased in caudate nucleus, while in thalamus major findings are increased levels of lipid peroxides and GR activity and decreased gamma-GCL activity. It can be concluded that perinatal PCP administration produces long-term alteration of antioxidant defense. Further studies are necessary in order to clarify role of redox dysregulation in the pathogenetic mechanism of schizophrenia.