Lara Canever

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 Bloods for serum BDNF were withdrawn 24h after the end of behavioral tasks.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 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.

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.

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

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.

Olfactory deficit as a result of clozapine withdrawal syndrome in an animal model of schizophrenia: preliminary results

Clozapine is an antipsychotic that produces serious withdrawal effects in schizophrenic patients. Olfactory deficits are well known as part of negative symptoms, but it is not known whether antipsychotic use and/or withdrawal are implicated. Then, we tested clozapine withdrawal in association with two widely used schizophrenia models: Neonatal immune challenge by Polycitidilic-polyinosinic acid (polyI:C) and ketamine. PolyI:C (or saline) was injected subcutaneously in neonatal period, dose of 5 mg/kg from 2 to 6 Post Natal Days, and ketamine or saline at the dose 25mg/kg intraperitoneally (i.p.), daily for 7 days from 53 to 60 post natal day. Clozapine 10mg/kg (or saline) was administered i.p. from 46 to 60 post natal day. Olfactory discrimination test (sensorial and cognitive deficit) was performed at 61 post natal day, 24h after the last injections. The association of PolyI:C, ketamine and clozapine disrupted Olfactory Discrimination, equating time in familiar and non-familiar compartments. PolyI:C plus ketamine increased crossings between compartments. It was produced, for the first time, an olfactory deficit induced by clozapine withdrawal in Wistar rats subjected to schizophrenia animal models.

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.

INVOLVEMENT OF NEUROINFLAMMATION IN THE MEMORY OF ADULT AND OLD OFFSPRING FROM WISTAR RATS WITH FOLIC ACID DEFICIENCY OR SUPPLEMENTATION DURING PREGNANCY

also show that glycolysis in Ab+LPS stimulated cells was significantly greater in PBMCs from IQ-dis individuals compared with IQ-con individuals. It is known that phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a significant driver of glycolysis because it increases PFKFB1 activity, which converts fructose-6-phosphate to fructose-1, 6-bisphosphate. The data show that PFKFB3 mRNA was also increased in PBMCs from IQ-dis individuals and a significant increase in the ratio of PFKFB3/PFKFB1 was also observed. Conclusions: We conclude that the metabolic shift towards glycolysis on PBMCs could represent a potential biomarker assay for the detection of early cognitive decline.