RESUMO
INTRODUCTION: Schizophrenia is considered one of the most disabling and severe human diseases worldwide. The etiology of schizophrenia is thought to be multifactorial and evidence suggests that DNA methylation can play an important role in underlying pivotal neurobiological alterations of this disorder. Some studies have demonstrated the effects of dietary supplementation as an alternative approach to the prevention of schizophrenia, including folic acid. However, no study has ever investigated the role of such supplementation in altering the DNA methylation system in the context of schizophrenia. OBJECTIVES: The present study aims to investigate the effects of maternal folic acid supplementation at different doses on nuclear methyltransferase activity of adult rat offspring subjected to an animal model schizophrenia induced by ketamine. METHODS: Adult female Wistar rats, (60 days old) received folic acid-deficient diet, control diet, or control diet plus folic acid supplementation (at 5, 10, or 50 mg/kg) during pregnancy and lactation. After reaching adulthood (60 days), the male offspring of these dams were subjected to the animal model of schizophrenia induced by 7 days of ketamine intraperitoneal injection (25 mg/kg). After the 7-day protocol, the activity of nuclear methyltransferase was evaluated in the brains of the offspring. RESULTS: Maternal folic acid supplementation at 50 mg/kg increased methyltransferase activity in the frontal cortex, while 10 mg/kg increased methyltransferase activity in the hippocampus. In the striatum of offspring treated with ketamine, maternal deficient diet, control diet, and folic acid supplementation at 5 mg/kg decreased methyltransferase activity compared to the control group. The folic acid supplementation at 10 and 50 mg/kg reversed this ketamine effect. CONCLUSIONS: Maternal FA deficiency could be related to schizophrenia pathophysiology, while FA supplementation could present a protective effect since it demonstrated persistent effects in epigenetic parameters in adult offspring.
Assuntos
Núcleo Celular/enzimologia , Ácido Fólico/uso terapêutico , Metiltransferases/metabolismo , Esquizofrenia/prevenção & controle , Animais , Núcleo Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Dieta , Suplementos Nutricionais , Feminino , Deficiência de Ácido Fólico/complicações , Ketamina , Masculino , Gravidez , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente , Esquizofrenia/enzimologia , Psicologia do EsquizofrênicoRESUMO
INTRODUCTION: D-amino-acid oxidase (DAAO) degrades D-serine, a co-agonist of the NMDA receptor whose dysfunction is involved in the positive, negative, and cognitive symptoms of schizophrenia. The inhibition of DAAO appears to be a viable strategy to increase D-serine level and to have therapeutic potential in schizophrenia. Areas covered: This review describes the efforts to develop DAAO inhibitors and to optimize their in vitro and in vivo effects in preclinical settings. The structural evolution of DAAO inhibitors is presented from simple carboxylic acid derivatives via small, planar compounds with carboxylic acid mimetics to extended compounds whose binding is possible owing to DAAO flexibility. Inhibitory potency and pharmacokinetic properties are discussed in the context of compounds' ability to increase D-serine level and to show efficacy in animal models of schizophrenia. Expert opinion: The accumulated knowledge on the structural requirements of DAAO inhibitors and on their in vitro and in vivo effects provides appropriate basis to develop inhibitors with optimized potency, selectivity and pharmacokinetic profile including blood-brain penetration. In addition, the validation of DAAO inhibition therapy in alleviating the symptoms of schizophrenia requires further studies on the efficacy of DAAO inhibitors in behavioral assays of animals and on the species differences in D-serine metabolism.
Assuntos
Antipsicóticos/farmacologia , D-Aminoácido Oxidase/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Animais , Modelos Animais de Doenças , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Humanos , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/enzimologia , Esquizofrenia/fisiopatologia , Serina/metabolismo , Especificidade da EspécieRESUMO
Schizophrenia is associated with shortening of the lifespan mainly due to cardiovascular events, cancer and chronic obstructive pulmonary disease. Both telomere attrition and decrease of telomerase levels were observed in schizophrenia. Polyunsaturated fatty acids (PUFA) influence multiple biochemical mechanisms which are postulated to accelerate telomere shortening and limit the longevity of patients with schizophrenia. Intervention studies based on add-on therapy with n-3 polyunsaturated fatty acids (n-3 PUFA) in patients with schizophrenia did not assess the changes in telomerase levels. A randomized placebo-controlled trial named OFFER was designed to compare the efficacy of a 26-week intervention composed of either 2.2g/day of n-3 PUFA or olive oil placebo with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between the clinical effect of n-3 PUFA and changes in telomerase levels. Seventy-one patients aged 16-35 were enrolled in the study and randomly assigned to the study arms. The Positive and Negative Syndrome Scale (PANSS) was used to assess the change in symptom severity. Telomerase levels of peripheral blood mononuclear cells (PBMC) were assessed at three points: at baseline and at weeks 8 and 26 of the intervention. A significantly greater increase in PBMC telomerase levels in the intervention group compared to placebo was observed (p<0.001). Changes in telomerase levels significantly and inversely correlated with improvement in depressive symptoms and severity of the illness. The efficacy of a six-month intervention with n-3 PUFA observed in first-episode schizophrenia may be related to an increase in telomerase levels.
Assuntos
Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Esquizofrenia/enzimologia , Esquizofrenia/terapia , Telomerase/sangue , Adolescente , Adulto , Antipsicóticos/uso terapêutico , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Masculino , Azeite de Oliva/administração & dosagem , Efeito Placebo , Escalas de Graduação Psiquiátrica , Esquizofrenia/sangue , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
We investigated whether ginsenoside Re (Re) modulates phencyclidine (PCP)-induced sociability deficits and recognition memory impairments to extend our recent finding. We examined the role of GPx-1 gene in the pharmacological activity of Re against mitochondrial dysfunction induced by PCP in the dorsolateral cortex of mice. Since mitochondrial oxidative stress activates NADPH oxidase (PHOX), we applied PHOX inhibitor apocynin for evaluating interactive modulation between GPx-1 and PHOX against PCP neurotoxicity. Sociability deficits and recognition memory impairments induced by PCP were more pronounced in GPx-1 knockout (KO) than in wild type (WT) mice. PCP-induced mitochondrial oxidative stress, mitochondrial dysfunction, and membrane translocation of p47phox were more evident in GPx-1 KO than in WT. Re treatment significantly attenuated PCP-induced neurotoxic changes. Re also significantly attenuated PCP-induced sociability deficits and recognition memory impairments. The attenuation by Re was comparable to that by apocynin. The attenuation was more obvious in GPx-1 KO than in WT. Importantly, apocynin did not show any additional positive effects on the neuroprotective activity of Re, indicating that PHOX is a molecular target for therapeutic activity of Re. Our results suggest that Re requires interactive modulation between GPx activity and PHOX (p47phox) to exhibit neuroprotective potentials against PCP insult.
Assuntos
Córtex Cerebral/enzimologia , Ginsenosídeos/administração & dosagem , Glutationa Peroxidase/metabolismo , Mitocôndrias/efeitos dos fármacos , NADPH Oxidases/metabolismo , Panax/química , Fenciclidina/efeitos adversos , Substâncias Protetoras/administração & dosagem , Esquizofrenia/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , NADPH Oxidases/genética , Estresse Oxidativo/efeitos dos fármacos , Esquizofrenia/enzimologia , Esquizofrenia/genética , Psicologia do Esquizofrênico , Glutationa Peroxidase GPX1RESUMO
ABSTRACT Studies have shown that schizophrenic patients seem to have nutritional deficiencies. Ascorbic acid (AA) has an important antioxidant effect and neuromodulatory properties. The aim of this study was to evaluate the effects of AA on locomotor activity and the acetylcholinesterase activity (AChE) in an animal model of schizophrenia (SZ). Rats were supplemented with AA (0.1, 1, or 10 mg/kg), or water for 14 days (gavage). Between the 9th and 15th days, the animals received Ketamine (Ket) (25 mg/kg) or saline (i.p). After the last administration (30 min) rats were subjected to the behavioral test. Brain structures were dissected for biochemical analysis. There was a significant increase in the locomotor activity in Ket treated. AA prevented the hyperlocomotion induced by ket. Ket also showed an increase of AChE activity within the prefrontal cortex and striatum prevented by AA. Our data indicates an effect for AA in preventing alterations induced by Ket in an animal model of SZ, suggesting that it may be an adjuvant approach for the development of new therapeutic strategies within this psychiatric disorder.
Assuntos
Animais , Masculino , Acetilcolinesterase/análise , Acetilcolinesterase/efeitos dos fármacos , Ácido Ascórbico/farmacologia , Esquizofrenia/enzimologia , Locomoção/efeitos dos fármacos , Antioxidantes/farmacologia , Acetilcolinesterase/fisiologia , Esquizofrenia/prevenção & controle , Antagonistas de Aminoácidos Excitatórios , Suplementos Nutricionais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Ketamina , Locomoção/fisiologiaRESUMO
Studies have shown that schizophrenic patients seem to have nutritional deficiencies. Ascorbic acid (AA) has an important antioxidant effect and neuromodulatory properties. The aim of this study was to evaluate the effects of AA on locomotor activity and the acetylcholinesterase activity (AChE) in an animal model of schizophrenia (SZ). Rats were supplemented with AA (0.1, 1, or 10 mg/kg), or water for 14 days (gavage). Between the 9th and 15th days, the animals received Ketamine (Ket) (25 mg/kg) or saline (i.p). After the last administration (30 min) rats were subjected to the behavioral test. Brain structures were dissected for biochemical analysis. There was a significant increase in the locomotor activity in Ket treated. AA prevented the hyperlocomotion induced by ket. Ket also showed an increase of AChE activity within the prefrontal cortex and striatum prevented by AA. Our data indicates an effect for AA in preventing alterations induced by Ket in an animal model of SZ, suggesting that it may be an adjuvant approach for the development of new therapeutic strategies within this psychiatric disorder.
Assuntos
Acetilcolinesterase/análise , Acetilcolinesterase/efeitos dos fármacos , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Locomoção/efeitos dos fármacos , Esquizofrenia/enzimologia , Esquizofrenia/prevenção & controle , Acetilcolinesterase/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Suplementos Nutricionais , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Ketamina , Locomoção/fisiologia , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/enzimologia , Ratos Wistar , Valores de Referência , Reprodutibilidade dos Testes , Esquizofrenia/induzido quimicamente , Esquizofrenia/fisiopatologiaRESUMO
AIMS: Schizophrenia is a debilitating neurodevelopmental disorder that is associated with dysfunction in the cholinergic system. Early prevention is a target of treatment to improve long-term outcomes. Therefore, we evaluated the preventive effects of omega-3 fatty acids on AChE activity in the prefrontal cortex, hippocampus and striatum in an animal model of schizophrenia. MAIN METHODS: Young Wistar rats (30 days old) were initially treated with omega-3 fatty acids or vehicle alone. Animals received ketamine to induce an animal model of schizophrenia or saline plus omega-3 fatty acids or vehicle alone for 7 consecutive days beginning on day 15. A total of 22 days elapsed between the treatment and intervention. Animals were sacrificed, and brain structures were dissected to evaluate AChE activity and gene expression. KEY FINDINGS: Our results demonstrate that ketamine increased AChE activity in these three structures, and omega-3 fatty acids plus ketamine showed lower values for the studied parameters, which indicate a partial preventive mechanism of omega-3 fatty acid supplementation. We observed no effect on AChE expression. Together, these results indicate that omega-3 fatty acid supplementation effectively reduced AChE activity in an animal model of schizophrenia in all studied structures. In conclusion, the present study provides evidence that ketamine and omega-3 fatty acids affect the cholinergic system, and this effect may be associated with the physiopathology of schizophrenia. Further studies are required to investigate the mechanisms that are associated with this effect.
Assuntos
Acetilcolinesterase/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Ketamina/antagonistas & inibidores , Ketamina/farmacologia , Esquizofrenia/enzimologia , Acetilcolinesterase/genética , Animais , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Masculino , Neostriado/efeitos dos fármacos , Neostriado/enzimologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/enzimologia , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamenteRESUMO
BACKGROUND: D-Serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, is synthesized from L-serine by serine racemase (SRR). Given the role of D-serine in both neurodevelopment and the pathophysiology of schizophrenia, we examined whether neonatal disruption of D-serine synthesis by SRR inhibition could induce behavioral abnormalities relevant to schizophrenia, in later life. METHODOLOGY/PRINCIPAL FINDINGS: Neonatal mice (7-9 days) were injected with vehicle or phenazine methosulfate (Met-Phen: 3 mg/kg/day), an SRR inhibitor. Behavioral evaluations, such as spontaneous locomotion, novel object recognition test (NORT), and prepulse inhibition (PPI) were performed at juvenile (5-6 weeks old) and adult (10-12 weeks old) stages. In addition, we tested the effects of D-serine on PPI deficits in adult mice after neonatal Met-Phen exposure. Finally, we assessed whether D-serine could prevent the onset of schizophrenia-like behavior in these mice. Neonatal Met-Phen treatment reduced D-serine levels in the brain, 24 hours after the final dose. Additionally, this treatment caused behavioral abnormalities relevant to prodromal symptoms in juveniles and to schizophrenia in adults. A single dose of D-serine improved PPI deficits in adult mice. Interestingly, chronic administration of D-serine (900 mg/kg/day from P35 to P70) significantly prevented the onset of PPI deficits after neonatal Met-Phen exposure. CONCLUSIONS/SIGNIFICANCE: This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life. Furthermore, early pharmacological intervention with D-serine may prevent the onset of psychosis in adult.
Assuntos
Antipsicóticos/administração & dosagem , Racemases e Epimerases/antagonistas & inibidores , Esquizofrenia/enzimologia , Serina/administração & dosagem , Estimulação Acústica , Animais , Animais Recém-Nascidos , Cerebelo/metabolismo , Feminino , Lobo Frontal/metabolismo , Locomoção , Masculino , Metilfenazônio Metossulfato , Camundongos , Racemases e Epimerases/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/induzido quimicamente , Esquizofrenia/prevenção & controle , Serina/metabolismoRESUMO
David Horrobin's membrane phospholipid theory of schizophrenia has held up well over time because his therapeutic prediction that dietary supplementation with eicosapentaenoic acid (EPA) would have a therapeutic effect has been partially verified and undergoes continued testing. In the final version of his theory, he hypothesized that there was hyperactivity of phosphoslipase A(2) (PLA(2)) or a related enzyme but did not explain how the hyperactivity came about. It is known that serotonergic 5HT(2A/2C) receptors are coupled to PLA(2), which hydrolyzes both arachidonic acid (AA) and EPA from diacylglycerides at the sn-2 position. In this paper, Horrobin's theory is combined with a previously published theory of chronic stress in which it was hypothesized that a disinhibited dorsal raphe nucleus, the principal nucleus of the serotonergic system, can organize the neuropathology of diseases such as migraine, hypertension, and the metabolic syndrome. The new or combined theory is that schizophrenia is a disease of chronic stress in which a disinhibited DRN causes widespread serotonergic overdrive in the cerebral cortex. This in turn causes overdrive of cPLA(2) and both central and peripheral depletion of AA and EPA. Because EPA is present in smaller amounts, it falls below threshold for maintaining an intracellular balance between AA-derived and EPA-derived second messenger cascades, which leads to abnormal patterns of neuronal firing. There are two causes of neuronal dysfunction: the disinhibited DRN and EPA depletion. Schizophrenia is statistically associated with metabolic syndrome, hypertension, and migraine because they form a cluster of diseases with similar pathophysiology. The theory provides an explanation for both the central and peripheral phospholipid abnormalities in schizophrenia. It also explains the role of stress in schizophrenia, elevated serum PLA(2) activity in schizophrenia, the relationship between untreated schizophrenia and metabolic syndrome, and the therapeutic rationale for EPA.
Assuntos
Encéfalo/enzimologia , Citosol/enzimologia , Lipídeos de Membrana/fisiologia , Fosfolipases A2/metabolismo , Fosfolipídeos/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Esquizofrenia/fisiopatologia , Estresse Psicológico/fisiopatologia , Humanos , Espectroscopia de Ressonância Magnética , Modelos Teóricos , Esquizofrenia/enzimologia , Estresse Psicológico/enzimologiaRESUMO
OBJECTIVES: Mounting evidence shows that oxidative stress (OS) and the purine/adenosine system play a key role in the pathophysiology of schizophrenia. Lately, our group pointed out that not only antioxidants, but also the prooxidant system plays an important role in neuro-psychiatric disorders. Xanthine oxidase (XO) is an enzyme of special interest in this context, since it acts as a prooxidant, but its main product is a vastly important antioxidant, uric acid (UA). Furthermore, XO plays major part in the purine/adenosine metabolism, which has been hypothesised to play a role in schizophrenia as well. METHODS: We examined the activity of XO in the striato-cortico-limbic system of schizophrenic patients (SP) and controls using a commercially available activity assay. RESULTS: We found decreased activity of XO in the occipital cortex and thalamus of patients with psychosis. Furthermore, XO shows a significant positive correlation with chlorpromazine equivalents in the putamen and the temporal cortex. CONCLUSIONS: Nevertheless, our results might suggest a downregulation of cellular defence mechanisms in schizophrenia in several brain regions, which could account for neuronal alterations which have been described before. This demonstrates that more research is needed to fully understand the role of the complex enzyme XO in the pathophysiology of schizophrenia.
Assuntos
Lobo Occipital/enzimologia , Esquizofrenia/enzimologia , Tálamo/enzimologia , Xantina Oxidase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Occipital/metabolismo , Estresse Oxidativo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Tálamo/metabolismo , Xantina Oxidase/fisiologiaRESUMO
An important risk gene in schizophrenia is D-: amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1-3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local D-: serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples.
Assuntos
D-Aminoácido Oxidase/metabolismo , Giro Denteado/enzimologia , Esquizofrenia/enzimologia , Idoso , Córtex Cerebral/enzimologia , Córtex Cerebral/metabolismo , D-Aminoácido Oxidase/genética , Giro Denteado/metabolismo , Feminino , Lateralidade Funcional , Expressão Gênica , Humanos , Hibridização In Situ , Masculino , Fibras Nervosas Mielinizadas/enzimologia , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Amielínicas/enzimologia , Fibras Nervosas Amielínicas/metabolismo , RNA Mensageiro/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Tálamo/enzimologia , Tálamo/metabolismoRESUMO
OBJECTIVE: To investigate the effects of Ginkgo biloba extract (EGb) administration on T lymphocyte subsets and superoxide dismutase (SOD) levels in schizophrenia. METHODS: One hundred and nine schizophrenic inpatients were randomly assigned to 12 weeks of treatment with 360 mg/day of EGb plus a stable dose of 0.25 mg kg(-1) day(-1) of haloperidol and placebo plus the same dose of haloperidol using a double-blind design. Clinical efficacy was determined using the Brief Psychiatric Rating Scale (BPRS), Scale for Assessment of Positive Symptoms, and Scale for Assessment of Negative Symptoms. T lymphocytes (CD3+), T helper cells (CD4+), T suppressor cells (CD8+), and IL-2-secreting cells were measured using the alkaline phosphatase/antialkaline phosphatase technique; and SOD levels were measured by radioimmunometric assay at baseline and at posttreatment, as compared to 30 sex- and age-matched normal subjects. RESULTS: Patients demonstrated significantly lower CD3+, CD4+, and IL-2-secreting cells, together with CD4/CD8 ratio, and significantly higher blood SOD levels than did healthy controls at baseline. There was a significantly negative relationship between SOD and CD4+ cells in the schizophrenic group at baseline. After a 12-week treatment, CD3+, CD4+, and IL-2-secreting cells, together with CD4/CD8 ratio, showed a significant increase, but a significant decrease in SOD levels in the EGb group. There was only a significant increase in CD4+ cells but no change in SOD levels in the placebo group. There was a significant correlation between the change in CD4+ cells at posttreatment vs pretreatment and a reduction of BPRS total score in the whole patient group. CONCLUSIONS: EGb may improve the decreased peripheral immune functions in schizophrenia. The beneficial effects of EGb on the immune systems and the improvement of schizophrenic symptoms may be medicated through its antioxidant activity.
Assuntos
Antioxidantes/uso terapêutico , Antipsicóticos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Ginkgo biloba , Haloperidol/uso terapêutico , Esquizofrenia/tratamento farmacológico , Subpopulações de Linfócitos T/efeitos dos fármacos , Adulto , Antioxidantes/farmacologia , Antipsicóticos/farmacologia , Escalas de Graduação Psiquiátrica Breve , Complexo CD3/análise , Contagem de Linfócito CD4 , Relação CD4-CD8 , Doença Crônica , Método Duplo-Cego , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Haloperidol/farmacologia , Humanos , Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Esquizofrenia/enzimologia , Esquizofrenia/imunologia , Psicologia do Esquizofrênico , Superóxido Dismutase/sangue , Fatores de Tempo , Resultado do TratamentoRESUMO
Depression is frequently associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to repeated episodes of hypercortisolemia. Hypothalamic paraventricular neurons are believed to trigger these processes by aberrant generation and/or release of corticotropin releasing hormone, oxytocin, vasopressin, and nitric oxide (NO). Recent findings from two independent laboratories have demonstrated that the suprachiasmatic nucleus, which in part controls the cellular activity of paraventricular neurons (PVN), is also involved in affective disorder. The aim of the present study was to elucidate by stereological analysis, whether suprachiasmatic nucleus (SCN) nitric oxide synthase and neurophysin generating neurons are affected in neuropsychiatric disorders. We show that compared to controls the number of nitric oxide synthase immunoreactive neurons is greatly reduced both in depression and in schizophrenia. In subjects with affective disorder there was a correlation between the number of NOS-expressing cells and duration of treatment with antidepressants. The number of neurophysin-expressing SCN neurons was also fewer in cases with mood disorder. It is concluded that SCN-derived NO may be a relevant pathophysiological factor in neuropsychiatric disorders.
Assuntos
Hipotálamo/enzimologia , Transtornos do Humor/enzimologia , Neurônios/enzimologia , Neurofisinas/metabolismo , Óxido Nítrico Sintase/metabolismo , Núcleo Supraquiasmático/enzimologia , Adulto , Depressão/enzimologia , Depressão/metabolismo , Depressão/patologia , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/patologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Hipotálamo/metabolismo , Hipotálamo/patologia , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/metabolismo , Transtornos do Humor/patologia , Neurônios/metabolismo , Neurônios/patologia , Óxido Nítrico Sintase/biossíntese , Esquizofrenia/enzimologia , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Núcleo Supraquiasmático/química , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/fisiopatologiaRESUMO
Numerous molecules enable the handling of glutamate that is destined for neurotransmitter release, including transporters, receptors and glutamatergic enzymes. Previous work in our lab has shown altered levels of transcript expression of excitatory amino acid transporters and a vesicular glutamate transporter in the thalamus in schizophrenia. These changes suggest that molecules that facilitate the release and reuptake of glutamate may be abnormal in schizophrenia. In this study we determined the levels of expression of phosphate activated glutaminase (PAG), which converts glutamine to glutamate, and glutamine synthetase (GS), which converts glutamate to glutamine, with the hypothesis that thalamic PAG and GS transcript expression is altered in schizophrenia. We investigated expression of PAG and GS mRNA using in situ hybridization in six different thalamic nuclei (anterior, dorsomedial, centromedial, ventral anterior, ventral and reticular) from 13 persons with schizophrenia and 8 comparison subjects and found that transcripts for PAG and GS were significantly increased in schizophrenia. Increased PAG and GS transcripts suggest enhanced glutamatergic neurotransmission in the thalamus and its efferent targets in schizophrenia.
Assuntos
Glutamato-Amônia Ligase/biossíntese , Glutaminase/biossíntese , RNA Mensageiro/metabolismo , Esquizofrenia/enzimologia , Tálamo/enzimologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Transcrição GênicaRESUMO
It has been suggested that the extract of gingko biloba (EGb) may enhance the efficiency of the classic antipsychotic haloperidol in patients with chronic schizophrenia, especially on positive symptoms, and reduce serum superoxide dismutase (SOD) levels. Therefore, we decided to evaluate the therapeutic effect of EGb and to examine the effect of it on the levels of antioxidant enzymes in schizophrenic patients on olanzapine treatment. We hypothesized that EGb would have the beneficial effects on schizophrenic symptoms and might cause reductions in antioxidant enzymes. The subjects were randomly assigned to the two groups: olanzapine plus EGb (group I) (n=15) and olanzapine alone (group II) (n=14). The patients were evaluated at baseline and at week 8 with respect to the Positive and Negative Syndrome Scale (PANSS), serum SOD, catalase (CAT), and glutathion peroxidase (GPX) levels. At baseline, no statistically significant difference regarding the mean total PANSS scores between treatment groups was found. At the evaluation of week 8, a significant difference in mean Scale for the Assessment of Postive Symptoms (SAPS) scores but not in Scale for the Assessment of Negative Symptoms scores between groups was found. Total patients had statistically significant higher serum SOD, CAT and GPX levels compared to control groups at baseline. At 8 weeks, there were significant differences in the mean decrease in SOD and CAT levels but not in GPX levels between treatment groups. The changes in SOD and CAT levels were correlated with the change in SAPS in group I, but not in the group II. The present study supported the findings of the previous study demonstrating that EGb might enhance the efficiency of antipsychotic in patients with schizophrenia, particularly on positive symptoms of the disorder.
Assuntos
Antioxidantes/metabolismo , Antipsicóticos/uso terapêutico , Ginkgo biloba , Esquizofrenia/tratamento farmacológico , Esquizofrenia/enzimologia , Adulto , Benzodiazepinas/uso terapêutico , Catalase/sangue , Quimioterapia Combinada , Eritrócitos/enzimologia , Feminino , Glutationa Peroxidase/sangue , Humanos , Masculino , Olanzapina , Extratos Vegetais/uso terapêutico , Escalas de Graduação Psiquiátrica , Método Simples-Cego , Superóxido Dismutase/sangueRESUMO
Impaired oxidative stress defense has been reported in blood of both drug-naïve and antipsychotic-treated patients suffering from schizophrenic psychosis, indicating the involvement of free radical metabolism in the pathogenetic processes of schizophrenia. In this study, the concentrations of two isoenzymes of superoxide dismutase (SOD), Cu, Zn- and MnSOD, were determined with ELISA in various cortical (frontal, parietal, temporal and occipital cortex) and subcortical areas (putamen, caudate nucleus, thalamus, and substantia innominata) of post-mortem brain tissue from patients diagnosed with a schizophrenia spectrum disorder and compared with those of controls. Post-mortem brain tissue from individuals without neuropsychiatric disorders served for control. Cu, Zn- and MnSOD levels were significantly increased in frontal cortex and substantia innominata of the index group, respectively. In all other areas both types of SOD remained virtually unchanged. Detection of SOD changes in the brain supports previous reports of alterations of antioxidant indices in blood cells of patients with schizophrenia and suggests a specific neuroanatomical distribution pattern of oxidative stress processes possibly related to the pathophysiology of schizophrenia.
Assuntos
Encéfalo/enzimologia , Estresse Oxidativo/fisiologia , Esquizofrenia/enzimologia , Superóxido Dismutase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antioxidantes/metabolismo , Encéfalo/fisiopatologia , Feminino , Lobo Frontal/enzimologia , Lobo Frontal/fisiopatologia , Humanos , Isoenzimas/química , Isoenzimas/metabolismo , Masculino , Pessoa de Meia-Idade , Esquizofrenia/fisiopatologia , Substância Inominada/enzimologia , Substância Inominada/fisiopatologia , Superóxido Dismutase/química , Regulação para Cima/fisiologiaRESUMO
Several types of evidence suggesting that the inflammatory response system is associated with pathophysiology of schizophrenia have been accumulated. Recently, a prospective double-blind study demonstrated that supplementary treatment with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, produced significantly greater improvement in scores on the Positive and Negative Syndrome Scale (PANSS) and on all subscales during the acute phase in patients with schizophrenia compared with risperidone alone therapy. The therapeutic effect of celecoxib on the psychopathology of schizophrenia is speculated to be based on COX activity inhibition; however, the detailed pharmacological mechanisms are unclear. To clarify whether or not COX-2 expression is altered in schizophrenia, we examined neuronal COX-2 expression in the hippocampus from cases of schizophrenia (n = 17), normal controls (n = 22), and cases of Alzheimer's disease (AD) as a positive control (n = 17). Quantitative immunohistochemical analysis demonstrated that neuronal COX-2 expression was significantly up-regulated in each CA1-4 region in Alzheimer's disease compared with controls, and that the mean COX-2 immunointensity in CA1-4 was significantly correlated with Abeta load in cases of Alzheimer's disease. In contrast, COX-2 expression was not up-regulated in any subdivision of the hippocampus in the schizophrenia group. These results suggest that celecoxib may affect the pathophysiology of schizophrenia through COX-2-independent actions rather than by inhibiting activity of up-regulated COX-2 protein.
Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Hipocampo/enzimologia , Isoenzimas/biossíntese , Neurônios/enzimologia , Prostaglandina-Endoperóxido Sintases/biossíntese , Esquizofrenia/enzimologia , Sulfonamidas/farmacologia , Idoso , Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/biossíntese , Autopsia , Celecoxib , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Feminino , Hipocampo/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Masculino , Proteínas de Membrana , Escalas de Graduação Psiquiátrica , Pirazóis , Esquizofrenia/tratamento farmacológico , Regulação para CimaRESUMO
Oxidative stress-mediated cell damage has been considered in the pathophysiology of schizophrenia. Abnormal findings have often been considered related to differences in ethnicity, life style, dietary patterns and medications, all of which influence indices of oxidative stress and oxidative cell damage. To minimize these confounds, schizophrenic patients were compared with age-matched control subjects with the same ethnic background and similar lifestyle, as well as with bipolar mood disorder (BMD) patients. Levels of antioxidant defense enzymes (i.e. superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GPx) were lower in schizophrenic patients than in controls, indicating conditions for increased oxidative stress. The contents of plasma thiobarbituric acid reactive substances (TBARS) were only marginally higher in schizophrenic patients, who had normal levels of arachidonic acid (AA), a major source of TBARS, indicating no significant oxidative membrane lipid peroxidation. Levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), however, were significantly lower in schizophrenic patients. When the same indices in BMD patients were compared with findings in matched controls, levels of only SOD and CAT were lower in the patients, whereas GPx was not. Again, as in schizophrenia, the contents of TBARS were marginally higher in BMD patients with no change in levels of AA. Levels of alpha-linolenic acid and EPA were significantly lower and levels of DHA were slightly lower in BMD patients. These data indicate that certain biochemical characteristics may be common to a spectrum of psychiatric disorders, and suggest supplementation of antioxidants and essential fatty acids might affect clinical outcome.
Assuntos
Antioxidantes/metabolismo , Transtorno Bipolar/enzimologia , Membrana Celular/metabolismo , Eritrócitos/enzimologia , Ácidos Graxos Insaturados/metabolismo , Esquizofrenia/enzimologia , Adulto , Afeto , Apolipoproteínas A/sangue , Apolipoproteínas B/sangue , Transtorno Bipolar/diagnóstico , Escalas de Graduação Psiquiátrica Breve , Catalase/metabolismo , Membrana Celular/patologia , Colesterol/sangue , Eritrócitos/patologia , Ácidos Graxos Essenciais/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Humanos , Masculino , Estresse Oxidativo/fisiologia , Esquizofrenia/diagnóstico , Esquizofrenia/fisiopatologia , Índice de Gravidade de Doença , Superóxido Dismutase/metabolismo , Triglicerídeos/sangue , Escalas de WechslerRESUMO
Schizophrenia has been associated with dysfunction of glutamatergic neurotransmission. Synaptic glutamate activates pre- and postsynaptic ionotropic NMDA, AMPA, and kainate and metabotropic receptors, is removed from the synapse via five cell surface-expressed transporters, and is packaged for release by three vesicular transporters. In addition, there is a family of intracellular molecules enriched in the postsynaptic density (PSD) that target glutamate receptors to the synaptic membrane, modulate receptor activity, and coordinate glutamate receptor-related signal transduction. Each family of PSD proteins is selective for a given glutamate receptor subtype, the most well characterized being the NMDA receptor binding proteins PSD93, PSD95, NF-L, and SAP102. Besides binding glutamate receptors, many of these proteins also interact with cell surface proteins like cell adhesion molecules, ion channels, cytoskeletal elements, and signal transduction molecules. Given the complexity of the glutamate neurotransmitter system, there are many locations where disruption of normal signaling could occur and give rise to abnormal glutamatergic neurotransmission in schizophrenia. Using multiple cohorts of postmortem tissue, we have examined these synaptic molecules in schizophrenic thalamus. The expression of NR1 and NR2C subunit transcripts is decreased in the thalamus in schizophrenia. Interestingly, three intracellular PSD molecules that link the NMDA receptor to signal transduction pathways are also abnormally expressed. Additionally, several of the cell surface and vesicular transporters are abnormal in the schizophrenic thalamus. While occasional findings of abnormal receptor expression are made, the most dramatic and consistent alterations that we have found in the thalamus in schizophrenia involve the family of intracellular signaling/scaffolding molecules. We propose that schizophrenia has a glutamatergic component that involves alterations in the intracellular machinery that is coupled to glutamate receptors, in addition to abnormalities of the receptors themselves. Our data suggest that schizophrenia is associated with abnormal glutamate receptor-related intracellular signaling in the thalamus, and point to novel targets for innovative drug discovery.
Assuntos
Glutamatos/fisiologia , Esquizofrenia/fisiopatologia , Sinapses/fisiologia , Tálamo/fisiopatologia , Sistema X-AG de Transporte de Aminoácidos/genética , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Humanos , N-Metilaspartato/fisiologia , Receptores de Glutamato/fisiologia , Esquizofrenia/enzimologia , Esquizofrenia/metabolismo , Transmissão Sináptica/fisiologia , Tálamo/enzimologia , Tálamo/metabolismoRESUMO
Glycogen synthase kinase-3 (GSK-3) (EC 2.7.1.37) is a protein kinase highly abundant in brain and involved in signal transduction cascades of multiple cellular processes, particularly neurodevelopment. Two forms of the enzyme, GSK-3alpha and -3beta have been previously identified. We have previously reported reduced GSK-3beta protein levels in postmortem frontal cortex of schizophrenic patients. In an attempt to explore whether reduction of GSK-3beta levels is brain region specific we examined it in occipital cortex. In order to find out if the reduction in frontal cortex is reflected in altered activity we measured GSK-3 enzymatic activity in this brain region. Western-blot analysis of GSK-3beta was carried out in postmortem occipital cortex of 15 schizophrenic, 15 bipolar, and 15 unipolar patients, and 15 normal controls. GSK-3 activity was measured by quantitating the phosphorylation of the specific substrate phospho-CREB in the frontal cortex specimens. GSK-3beta levels in occipital cortex did not differ between the four diagnostic groups. GSK-3 activity in the frontal cortex of schizophrenic patients was 45% lower than that of normal controls (0.196+/-0.082 and 0.357+/-0.084 pmol/mg proteinxmin, respectively; Kruskal-Wallis analysis: chi-square=8.27, df=3, p=0.04). The other two diagnostic groups showed no difference from the control group. Our results are consistent with the notion that schizophrenia involves neurodevelopmental pathology.