RESUMO
This study aimed to evaluate Haloperidol's (Hal) effects on the behavioral, neurotrophic factors, and epigenetic parameters in an animal model of schizophrenia (SCZ) induced by ketamine (Ket). Injections of Ket or saline were administered intraperitoneal (once a day) between the 1st and 14th days of the experiment. Water or Hal was administered via gavage between the 8th and 14th experimental days. Thirty minutes after the last injection, the animals were subjected to behavioral analysis. The activity of DNA methyltransferase (DNMT), histone deacetylase (HDAC), and histone acetyltransferase and levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. Ket increased the covered distance and time spent in the central area of the open field, and Hal did not reverse these behavioral alterations. Significant increases in the DNMT and HDAC activities were detected in the frontal cortex and striatum from rats that received Ket, Hal, or a combination thereof. Besides, Hal per se increased the activity of DNMT and HDAC in the hippocampus of rats. Hal per se or the association of Ket plus Hal decreased BDNF, NGF, NT-3, and GDNF, depending on the brain region and treatment regimen. The administration of Hal can alter the levels of neurotrophic factors and the activity of epigenetic enzymes, which can be a factor in the development of effect collateral in SCZ patients. However, the precise mechanisms involved in these alterations are still unclear.
Assuntos
Ketamina , Esquizofrenia , Humanos , Ratos , Animais , Haloperidol/farmacologia , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Ketamina/toxicidade , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Fator de Crescimento Neural/genética , Modelos Animais de Doenças , Epigênese GenéticaRESUMO
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
Schizophrenia is a chronic neuropsychiatric disorder with a poorly understood pathophysiology. The theories about the disorder are mainly about dysregulation in one or more systems of neurotransmitters, and the progression triggers the presence of inflammatory markers indicates the possibility that the disorder is initially an inflammatory disease. The objective was to evaluate the ascorbic acid supplementation in an animal model of schizophrenia, on behavioral parameters, and cytokines involved in inflammation IL-1ß, IL-10. Wistar rats with 60 days of age were used which were supplemented with ascorbic acid at 0.1, 1, and 10 mg/kg or saline for 14 days via orogastric gavage. Subsequently, four groups were given ketamine (25 mg/kg) and four groups received intraperitoneal saline from the 9th-15th day of the experiment. After 30 min of the last administration of ketamine/saline, and behavioral test, rats were killed by guillotine decapitation and the brain structures were carefully dissected for biochemical analysis. Results showed that ascorbic acid supplementation prevented motor sensory loss but nor alter other parameters evaluated. We concluded that ascorbic acid may be used as a therapeutic adjuvant in schizophrenia and may help to improve the schizophrenic patient's life quality.
Assuntos
Anestésicos Dissociativos , Ácido Ascórbico/uso terapêutico , Suplementos Nutricionais , Ketamina , Esquizofrenia/induzido quimicamente , Esquizofrenia/prevenção & controle , Vitaminas/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Citocinas , Relação Dose-Resposta a Droga , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratos , Ratos Wistar , Esquizofrenia/patologia , Psicologia do EsquizofrênicoRESUMO
An emerging area in schizophrenia research focuses on the impact of immunomodulatory drugs such as melatonin, which have played important roles in many biological systems and functions, and appears to be promising. The objective was to evaluate the effect of melatonin on behavioral parameters in an animal model of schizophrenia. For this, Wistar rats were divided and used in two different protocols. In the prevention protocol, the animals received 1 or 10mg/kg of melatonin or water for 14 days, and between the 8th and 14th day they received ketamine or saline. In the reversal protocol, the opposite occurred. On the 14th day, the animals underwent behavioral tests: locomotor activity and prepulse inhibition task. In both protocols, the results revealed that ketamine had effects on locomotor activity and prepulse inhibition, confirming the validity of ketamine construction as a good animal model of schizophrenia. However, at least at the doses used, melatonin was not able to reverse/prevent ketamine damage. More studies are necessary to evaluate the role of melatonin as an adjuvant treatment in psychiatric disorders.
Assuntos
Suplementos Nutricionais , Melatonina , Esquizofrenia , Animais , Comportamento Animal , Modelos Animais de Doenças , Melatonina/farmacologia , Ratos , Ratos Wistar , Roedores , Esquizofrenia/tratamento farmacológicoRESUMO
This study investigated the behavioral and biochemical parameters of DM1 as a risk factor in an animal model of schizophrenia (SZ). All groups: 1 Control (saline+saline); 2 Alloxan (alloxan+saline); 3 Ketamine (saline+ketamine); 4 (Alloxan+Ketamine) were fasted for a period of 18h before the subsequent induction of DM via a single intraperitoneal (i.p) injection of alloxan (150mg/kg). From the 4th to the 10th days, the animals were injected i.p with ketamine (25mg/kg) or saline, once a day, to induce a model of SZ and 30min after the last administration were subjected to behavioral testing. After, the animals were decapitated and the brain structures were removed. Ketamine induced hyperactivity and in the social interaction, ketamine, alloxan and the association of alloxan+ketamine increased the latency and decreased the number of contacts between animals. The animals from the ketamine, alloxan and alloxan+ketamine groups showed a prepulse startle reflex (PPI) deficit at the three intensities (65, 70 and 75dB). Ketamine was shown to be capable of increasing the activity of acetylcholinesterase (AChE) in the brain structures. Combination of alloxan+ketamine seems to have an exacerbated effect within the cholinergic system. For lipid peroxidation and protein carbonyls, alloxan+ketamine appear to have intensified lipid and protein damage in the three structures. Ketamine and the combination of ketamine+alloxan induced DNA damage in both frequency and damage index. This research found a relationship between DM1 and SZ.