Alexandra S. Heylmann

Effects of omega-3 dietary supplement in prevention of positive, negative and cognitive symptoms: A study in adolescent rats with ketamine-induced model of schizophrenia

Omega-3 has shown efficacy to prevent schizophrenia conversion in ultra-high risk population. We evaluated the efficacy of omega-3 in preventing ketamine-induced effects in an animal model of schizophrenia and its effect on brain-derived neurotrophic factor (BDNF). Omega-3 or vehicle was administered in Wistar male rats, both groups at the 30th day of life for 15days. Each group was split in two to receive along the following 7days ketamine or saline. Locomotor and exploratory activities, memory test and social interaction between pairs were evaluated at the 52nd day of life. Prefrontal-cortex, hippocampus and striatum tissues were extracted right after behavioral tasks for mRNA BDNF expression analysis. Bloods for serum BDNF were withdrawn 24h after the end of behavioral tasks. Locomotive was increased in ketamine-treated group compared to control, omega-3 and ketamine plus omega-3 groups. Ketamine group had fewer contacts and interaction compared to other groups. Working memory and short and long-term memories were significantly impaired in ketamine group compared to others. Serum BDNF levels were significantly higher in ketamine plus omega-3 group. There was no difference between groups in prefrontal-cortex, hippocampus and striatum for mRNA BDNF expression. Administration of omega-3 in adolescent rats prevents positive, negative and cognitive symptoms in a ketamine animal model of schizophrenia. Whether these findings are consequence of BDNF increase it is unclear. However, this study gives compelling evidence for larger clinical trials to confirm the use of omega-3 to prevent schizophrenia and for studies to reinforce the beneficial role of omega-3 in brain protection.

Omega-3 prevents behavior response and brain oxidative damage in the ketamine model of schizophrenia.

Supplementation with omega-3 has been identified as an adjunctive alternative for the treatment of psychiatric disorders, in order to minimize symptoms. Considering the lack of understanding concerning the pathophysiology of schizophrenia, the present study hypothesized that omega 3 prevents the onset of symptoms similar to schizophrenia in young Wistar rats submitted to ketamine treatment. Moreover, the role of oxidative stress in this model was assessed. Omega-3 (0.8g/kg) or vehicle was given by orogastric gavage once daily. Both treatments were performed during 21days, starting at the 30th day of life in young rats. After 14days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25mg/kg ip daily) was started and maintained until the last day of the experiment. We evaluated the pre-pulse inhibition of the startle reflex, activity of antioxidant systems and damage to proteins and lipids. Our results demonstrate that supplementation of omega-3 prevented: decreased inhibition of startle reflex, damage to lipids in the hippocampus and striatum and damage to proteins in the prefrontal cortex. Furthermore, these changes are associated with decreased GPx in brain tissues evaluated. Together, our results suggest the prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia.

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.

Effect of maternal deprivation on acetylcholinesterase activity and behavioral changes on the ketamine-induced animal model of schizophrenia

Maternal deprivation has been associated with physiological and developmental changes that may be related to an increased risk for childhood and adult neuropsychiatric diseases. A growing number of studies demonstrated the importance of childhood experiences in the development of psychosis and schizophrenia in adulthood. Therefore, the present study investigated different behavior responses in rats following maternal deprivation and/or ketamine treatment in adulthood. Male rats were subjected to maternal deprivation for 180 min from postnatal day-01 to postnatal day-10. We evaluated locomotor activity, avoidance task and social interaction of adult male rats deprived or not deprived that were administered with saline or acute subanesthetic doses of ketamine (5, 15 and 25 mg/kg, i.p.). Our results show that only ketamine (25 mg/kg, i.p.) treatment in the adult rats lead to hyperlocomotion but not ketamine (5 and 15 mg/kg) and maternal deprivation alone. However, maternally deprived rats treated with ketamine (5 mg/kg) induced hyperlocomotion. Additionally, ketamine (25 mg/kg) and maternal deprivation alone induced cognitive deficit in the avoidance task. Rats deprived of and treated with ketamine (5, 15 and 25 mg/kg) also lead to memory deficit. Moreover, ketamine (25 mg/kg) and maternal deprivation alone increased latency to start social behavior. However, ketamine (5 mg/kg) and maternal deprivation lead to an increase of latency to start social behavior. Biochemistry data showed that all doses of ketamine and ketamine plus maternal deprivation increased the acetylcholinesterase (AChE) activity in the prefrontal cortex, hippocampus and striatum. The major doses of ketamine associated with maternal deprivation induced a major increase of AChE activity. Together, our results suggest that animals subjected to maternal deprivation had an increased risk for schizophrenia-like behavior and cholinergic alteration.

Effects of omega-3 supplementation on interleukin and neurotrophin levels in an animal model of schizophrenia

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 rats 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 rats 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-1β and IL6. These findings suggest that the similarity of IL-1β 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.

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

ABSTRACT 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 7 days 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. HIGHLIGHTSCigarette smoke exposure in pregnant dams caused damage in offspring in adult age.Administration of ketamine and ketamine plus cigarette increased the locomotor activity.Administration of ketamine reproduced the negative symptoms of schizophrenia.Ketamine increased AchE activity in the brain structures.Cigarette smoke exposure increases the damage caused by ketamine administration alone.

Acute administration of fenproporex increased acetylcholinesterase activity in brain of young rats

Fenproporex is the second most commonly amphetamine-based anorectic consumed worldwide; this drug is rapidly converted into amphetamine, in vivo, and acts by increasing dopamine levels in the synaptic cleft. Considering that fenproporex effects on the central nervous system are still poorly known and that acetylcholinesterase is a regulatory enzyme which is involved in cholinergic synapses and may indirectly modulate the release of dopamine, the present study investigated the effects of acute administration of fenproporex on acetylcholinesterase activity in brain of young rats. Young male Wistar rats received a single injection of fenproporex (6.25, 12.5 or 25mg/kg i.p.) or vehicle (2% Tween 80). Two hours after the injection, the rats were killed by decapitation and the brain was removed for evaluation of acetylcholinesterase activity. Results showed that fenproporex administration increased acetylcholinesterase activity in the hippocampus and posterior cortex, whereas in the prefrontal cortex, striatum and cerebellum the enzyme activity was not altered. In conclusion, in the present study we demonstrated that acute administration of fenproporex exerts an effect in the cholinergic system causing an increase in the activity of acetylcholinesterase in a dose-dependent manner in the hippocampus and posterior cortex. Thus, we suggest that the imbalance in cholinergic homeostasis could be considered as an important pathophysiological mechanism underlying the brain damage observed in patients who use amphetamines such as fenproporex.

Pre-clinical investigation of Diabetes Mellitus as a risk factor for schizophrenia

HighlightsType 1 Diabetes Mellitus can be considered a predisposing factor for schizophrenia.Association alloxan + ketamine induced deficit in social interaction between animals.Alloxan + ketamine group showed a PPI deficit at all three intensities evaluated.Alloxan + ketamine seems to have an exacerbated effect within the cholinergic system.Combination alloxan + ketamine intensified oxidative damage in the brain structures. Abstract 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 18 h before the subsequent induction of DM via a single intraperitoneal (i.p) injection of alloxan (150 mg/kg). From the 4th to the 10th days, the animals were injected i.p with ketamine (25 mg/kg) or saline, once a day, to induce a model of SZ and 30 min 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 75 dB). 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.