RESUMEN
The incidence of schizophrenia in young adulthood may be associated with intrauterine factors, such as gestational alcohol consumption. This study investigated the relationship between a single high dose of alcohol during pregnancy in Wistar rats and the development of schizophrenia in the adult life of the offspring. On the 11th day of gestation, pregnant rats received either water or alcohol via intragastric gavage. Male and female offspring were subjected to behavioral tests at 30 days of age according to the maternal group. At 60 days of age, offspring received intraperitoneal injections of ketamine (ket) or saline (SAL). After the final ketamine administration, the adult offspring underwent behavioral tests, and their brain structures were removed for biochemical analysis. Alcohol binge drinking during pregnancy induces hyperlocomotion in both young female and male offspring, with males of alcohol-exposed mothers showing reduced social interactions. In adult offspring, ketamine induced hyperlocomotion; however, only females in the alcohol + ket group exhibited increased locomotor activity, and a decrease in the time to first contact was observed in the alcohol group. Cognitive impairment was exclusively observed in male animals in the alcohol group. Increased serotonin and dopamine levels were observed in male rats in the alcohol + ket group. Biochemical alterations indicate the effects of intrauterine alcohol exposure associated with ketamine in adult animals. These behavioral and biochemical changes suggest that the impact of prenatal stressors such as alcohol persists throughout the animals' lives and may be exacerbated by a second stressor in adulthood, such as ketamine.
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Many aspects of the impact of childhood trauma remain unknown, such as the age at which individuals are most vulnerable to trauma, whether traumatic experiences have more severe and lasting effects when experienced early in life, and whether early life trauma causes psychiatric conditions such as anxiety and major depressive disorder (MDD) that persist over time or evolve into other disorders. Thus, this study aimed to investigate the impact of traumatic experiences in childhood on susceptibility to mood disorders in adulthood, particularly MDD. Animal models were used to address these questions, and different stressor protocols at various stages of the offspring's life were used. Three-hit starting with injections of Poly: IC was performed on the 9th day of gestation and then considered the first stressor. After birth, the animals were exposed to the maternal deprivation (MD) protocol, which separated the pups from the mother 3 h a day during the first ten days of life. From the 60th day of life, the animals were divided to receive the chronic mild stress (CMS) protocol over 21 days. The stressors can induce anxiety-like behaviors, such as increased locomotor activity through a maternal immune activation protocol using Poly: IC and demonstrating depressive-like behaviors through the MD and CMS protocols. It also showed changes in brain structures for pro-inflammatory parameters, IL-1ß and TNF-α, and alterations in anti-inflammatory parameters, IL-4 and IL-10, at different ages of life. The study also found that regulating pro- and anti-inflammatory cytokines is necessary for appropriate neuronal behavior, and stress responses can be both friendly and enemy, with costs and benefits balanced to provide the best-fit result. In conclusion, phenotypic characteristics of animals' life history are shaped by signals transmitted directly or indirectly to developing animals, known as "predictive adaptive responses."
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Trastorno Depresivo Mayor , Trastornos Mentales , Humanos , Ratas , Animales , Encéfalo , Depresión/etiología , Estrés Psicológico/complicaciones , AntiinflamatoriosRESUMEN
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.
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Ketamina , Esquizofrenia , Humanos , Ratas , Animales , Haloperidol/farmacología , Esquizofrenia/inducido químicamente , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Ketamina/toxicidad , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado de la Línea Celular Glial , Factor de Crecimiento Nervioso/genética , Modelos Animales de Enfermedad , Epigénesis GenéticaRESUMEN
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.
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Núcleo Celular/enzimología , Ácido Fólico/uso terapéutico , Metiltransferasas/metabolismo , Esquizofrenia/prevención & control , Animales , Núcleo Celular/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Dieta , Suplementos Dietéticos , Femenino , Deficiencia de Ácido Fólico/complicaciones , Ketamina , Masculino , Embarazo , Ratas , Ratas Wistar , Esquizofrenia/inducido químicamente , Esquizofrenia/enzimología , Psicología del EsquizofrénicoRESUMEN
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.
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Anestésicos Disociativos , Ácido Ascórbico/uso terapéutico , Suplementos Dietéticos , Ketamina , Esquizofrenia/inducido químicamente , Esquizofrenia/prevención & control , Vitaminas/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/patología , Citocinas , Relación Dosis-Respuesta a Droga , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratas , Ratas Wistar , Esquizofrenia/patología , Psicología del EsquizofrénicoRESUMEN
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.
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Suplementos Dietéticos , Melatonina , Esquizofrenia , Animales , Conducta Animal , Modelos Animales de Enfermedad , Melatonina/farmacología , Ratas , Ratas Wistar , Roedores , Esquizofrenia/tratamiento farmacológicoRESUMEN
This study aimed to verify possible alterations involving histological and oxidative stress parameters in the lungs of wild bats in the Carboniferous Basin of Santa Catarina (CBSC) state, Southern Brazil, as a means to evaluate the impact of coal dust on the health of wildlife. Specimens of frugivorous bat species Artibeus lituratus and Sturnira lilium were collected from an area free of coal dust contamination and from coal mining areas. Chemical composition, histological parameters, synthesis of oxidants and antioxidant enzymes, and oxidative damage in the lungs of bats were analyzed. Levels of Na, Cl, Cu, and Br were higher in both species collected in the CBSC than in the controls. Levels of K and Rb were higher in A. lituratus, and levels of Si, Ca, and Fe were higher in S. lilium collected in the carboniferous basin. Both bat species inhabiting the CBSC areas exhibited an increase in the degree of pulmonary emphysema compared to their counterparts collected from control areas. Sturnira lilium showed increased reactive oxygen species (ROS) and 2',7'-dichlorofluorescein (DCF) levels, while A. lituratus showed a significant decrease in nitrite levels in the CBSC samples. Superoxide dismutase (SOD) activity did not change significantly; however, the activity of catalase (CAT) and levels of glutathione (GSH) decreased in the A. lituratus group from CBSC compared to those in the controls. There were no differences in NAD(P)H quinone dehydrogenase 1 protein (NQO1) abundance or nitrotyrosine expression among the different groups of bats. Total thiol levels showed a significant reduction in A. lituratus from CBSC, while the amount of malondialdehyde (MDA) was higher in both A. lituratus and S. lilium groups from coal mining areas. Our results suggested that bats, especially A. lituratus, living in the CBSC could be used as sentinel species for harmful effects of coal dust on the lungs.
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Quirópteros , Minas de Carbón , Carbón Mineral/toxicidad , Pulmón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Brasil , Catalasa/metabolismo , Quirópteros/anatomía & histología , Quirópteros/metabolismo , Polvo , Glutatión/metabolismo , Pulmón/anatomía & histología , Pulmón/química , Pulmón/metabolismo , Malondialdehído/metabolismo , Metales/análisis , Modelos Biológicos , Enfisema Pulmonar/veterinaria , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Early childhood schizophrenia (COS) is a rare condition and has no established animal model to test new treatments. Previous studies have shown that repeated doses of 25â¯mg/kg ketamine produce schizophrenia-like changes in adult male Wistar rats, but adequate doses of ketamine in animal COS studies are not yet known. Male and female Wistar rats, 23 days old, received an injection of ketamine or intraperitoneal saline (i.p.) for 8 days. The animals underwent different behavioral tests: open field, social interaction, pre-pulse startle inhibition (PPI). Female rats showed behavioral changes at all ketamine doses (5, 15, 25 and 50â¯mg/kg), in contrast to males that only at 50â¯mg/kg dose had interrupted PPI and higher stereotypy in the open field test. The present study demonstrated that ketamine at a dose of 50â¯mg/kg once daily from 23 to 31 days postnatal reproduced changes similar to schizophrenia in pre-pubertal male and female Wistar rats and could be used, with other interventions, in future studies with animals in COS.
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Conducta Animal/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/farmacología , Inhibición Prepulso/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Esquizofrenia , Conducta Estereotipada/efectos de los fármacosRESUMEN
Evidence suggest that prenatal immune system disturbance contributes largely to the pathophysiology of neuropsychiatric disorders. We investigated if maternal immune activation (MIA) could induce inflammatory alterations in fetal brain and pregnant rats. Adult rats subjected to MIA also were investigated to evaluate if ketamine potentiates the effects of infection. On gestational day 15, Wistar pregnant rats received lipopolysaccharide (LPS) to induce MIA. After 6, 12 and 24â¯h, fetus brain, placenta, and amniotic fluid were collected to evaluate early effects of LPS. MIA increased oxidative stress and expression of metalloproteinase in the amniotic fluid and fetal brain. The blood brain barrier (BBB) integrity in the hippocampus and cortex as well integrity of placental barrier (PB) in the placenta and fetus brain were dysregulated after LPS induction. We observed elevated pro- and anti-inflammatory cytokines after LPS in fetal brain. Other group of rats from postnatal day (PND) 54 after LPS received injection of ketamine at the doses of 5, 15, and 25â¯mg/kg. On PND 60 rats were subjected to the memories tests, spontaneous locomotor activity, and pre-pulse inhibition test (PPI). Rats that receive MIA plus ketamine had memory impairment and a deficit in the PPI. Neurotrophins were increased in the hippocampus and reduced in the prefrontal cortex in the LPS plus ketamine group. MIA induced oxidative stress and inflammatory changes that could be, at least in part, related to the dysfunction in the BBB and PB permeability of pregnant rats and offspring. Besides, this also generates behavioral deficits in the rat adulthood's that are potentiated by ketamine.
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Conducta Animal , Barrera Hematoencefálica/inmunología , Encéfalo , Citocinas/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Inflamación/inmunología , Ketamina/farmacología , Lipopolisacáridos/farmacología , Trastornos de la Memoria , Placenta/inmunología , Complicaciones del Embarazo/inmunología , Inhibición Prepulso , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/fisiopatología , Embrión de Mamíferos , Femenino , Inflamación/etiología , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/inmunología , Trastornos de la Memoria/fisiopatología , Embarazo , Complicaciones del Embarazo/inducido químicamente , Inhibición Prepulso/efectos de los fármacos , Inhibición Prepulso/fisiología , Ratas , Ratas WistarRESUMEN
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.
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Aloxano/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Tipo 1/complicaciones , Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/farmacología , Inhibición Prepulso/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Esquizofrenia/etiología , Conducta Social , Aloxano/administración & dosificación , Animales , Diabetes Mellitus Tipo 1/inducido químicamente , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Ketamina/administración & dosificación , Masculino , Ratas , Ratas Wistar , Factores de Riesgo , Esquizofrenia/inducido químicamenteRESUMEN
New studies suggest that polyunsaturated fatty acids, such as omega-3, may reduce the symptoms of schizophrenia. The present study evaluated the preventive effect of omega-3 on interleukines (IL) and neurotrophin brain-derived neurotrophic factor (BDNF) levels in the brains of young rats subjected to a model of schizophrenia. Treatment was performed over 21 days, starting on the 30th day of rat's life. After 14 days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25 mg/kg) was started and maintained until the last day of the experiment. BDNF levels in the rat's prefrontal cortex were decreased at 1 h and 24 h after the last administration of ketamine, whereas the group administered with ketamine and omega-3 showed a decrease in BDNF levels only after 24 h. In contrast, both interventions induced similar responses in levels of IL-1ß and IL6. These findings suggest that the similarity of IL-1ß and IL6 levels in our experimental groups is due to the mechanism of action of ketamine on the immune system. More studies have to be carried out to explain this pathology. In conclusion, according to previous studies and considering the current study, we could suggest a prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia.