Effects of maternal folic acid supplementation on nuclear methyltransferase activity of adult rats subjected to an animal model of schizophrenia.

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.

The preventive effects of ascorbic acid supplementation on locomotor and acetylcholinesterase activity in an animal model of schizophrenia induced by ketamine

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.

The preventive effects of ascorbic acid supplementation on locomotor and acetylcholinesterase activity in an animal model of schizophrenia induced by ketamine.

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.

Increased risk of developing schizophrenia in animals exposed to cigarette smoke during the gestational period.

Cigarette smoking during the prenatal period has been investigated as a causative factor of obstetric abnormalities, which lead to cognitive and behavioural changes associated with schizophrenia. The aim of this study was to investigate behaviour and AChE activity in brain structures in adult rats exposed to cigarette smoke during the prenatal period. Pregnant rats were divided into non-PCSE (non-prenatal cigarette smoke exposure) and PCSE (prenatal cigarette smoke exposure) groups. On post-natal day 60, the rats received saline or ketamine for 7days and were subjected to behavioural tasks. In the locomotor activity task, the non-PCSE+ketamine and PCSE+ketamine groups exhibited increased locomotor activity compared with the saline group. In the social interaction task, the non-PCSE+ketamine and PCSE+ketamine groups exhibited an increased latency compared with the control groups. However, the PCSE+ketamine group exhibited a decreased latency compared with the non-PCSE+ketamine group, which indicates that the cigarette exposure appeared to decrease, the social deficits generated by ketamine. In the inhibitory avoidance task, the non-PCSE+ketamine, PCSE, and PCSE+ketamine groups exhibited impairments in working memory, short-term memory, and long-term memory. In the pre-pulse inhibition (PPI) test, cigarette smoke associated with ketamine resulted in impaired PPI in 3 pre-pulse (PP) intensity groups compared with the control groups. In the biochemical analysis, the AChE activity in brain structures increased in the ketamine groups; however, the PCSE+ketamine group exhibited an exacerbated effect in all brain structures. The present study indicates that exposure to cigarette smoke during the prenatal period may affect behaviour and cerebral cholinergic structures during adulthood.

Effect of folic acid on oxidative stress and behavioral changes in the animal model of schizophrenia induced by ketamine.

Recent studies have shown benefits for the supplementation of folic acid in schizophrenic patients. The aim of this study was to evaluate the effects of folic acid addition on adult rats, over a period of 7 or 14 days. It also sets out to verify any potential protective action using an animal model of schizophrenia induced by ketamine, in behavioral and biochemical parameters. This study used two protocols (acute and chronic) for the administration of ketamine at a dose of 25 mg/kg (i.p.). The folic acid was given by oral route in doses of 5, 10 and 50 mg/kg, once daily, for 7 and/or 14 days in order to compare the protective effects of folic acid. Thirty minutes after the last administration of ketamine, the locomotor and social interaction activities were evaluated, and immediately the brain structure were removed for biochemical analysis. In this study, ketamine was administered in a single dose or in doses over the course of 7 days increasing the animal's locomotion. This study showed that the administration of folic acid over 7 days was unable to prevent hyper locomotion. In contrast, folic acid (10 and 50 mg/kg) administrated over a period of 14 days, was able to partially prevent the hyper locomotion. Our data indicates that both acute and chronic administrations of ketamine increased the time to first contact between the animals, while the increased latency for social contact was completely prevented by folic acid (5, 10 and 50 mg/kg). Chronic and acute administrations of ketamine also increased lipid peroxidation and protein carbonylation in brain. Folic acid (10 and 50 mg/kg) supplements showed protective effects on the oxidative damage found in the different brain structures evaluated. All together, the results indicate that nutritional supplementation with folic acid provides promising results in an animal model of schizophrenia induced by ketamine.

Omega-3 fatty acids prevent the ketamine-induced increase in acetylcholinesterase activity in an animal model of schizophrenia.

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.