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BACKGROUND: Several studies provide clear evidence that exposure to various infections during pregnancy are linked with an increased risk for schizophrenia. In preclinical studies, administration of polyinosinic-polycytidylic acid (Poly I:C) in pregnant rodents can induce maternal immune activation leading to impairments in brain function in the offspring. OBJECTIVES: The aim of this study was to investigate the effect of vortioxetine, a multimodal selective serotonin reuptake inhibitor (SSRI), in the pathophysiology of Poly I:C-induced schizophrenia-like model in rats. METHODS: For this purpose, Poly I:C (8 mg/kg, ip) was injected into pregnant animals 14 days after mating, and tail blood was taken for determination of IL-6 levels after 2 h. At postnatal days 83-86, behavioral tests were performed. RESULTS: Our results revealed that Poly I:C caused impairments in prepulse inhibition, novel object recognition, social interaction, and open-field tests. Chronic administration of vortioxetine (2.5, 5, and 10 mg/kg, ip, postnatal days 69-83) caused significant improvements in these deficits. CONCLUSION: Overall, our findings indicate that vortioxetine may provide new therapeutic approaches for the treatment of schizophrenia. We think that increased serotonergic activity in frontal brain regions may provide the ameliorative effect of vortioxetine, especially on negative and cognitive symptoms. Therefore, it will be useful to determine the efficacy of vortioxetine with combined drugs with further studies.

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Objectives: Autism is a devastating neurodevelopmental disorder and recent studies showed that omega-3 or astaxanthin might reduce autistic symptoms due to their anti-inflammatory properties. Therefore, we investigated the effects of omega-3 and astaxanthin on the VPA-induced autism model of rats.Material and Methods: Female Wistar albino pups (n = 40) were grouped as control, autistic, astaxanthin (2 mg/kg), omega-3 (200 mg/kg), and astaxanthin (2 mg/kg)+omega-3 (200 mg/kg). All groups except the control were prenatally exposed to VPA. Astaxanthin and omega-3 were orally administered from the postnatal day 41 to 68 and behavioral tests were performed between day 69 and 73. The rats were decapitated 24 h after the behavioral tests and hippocampal and prefrontal cytokines and 5-HT levels were analyzed by ELISA.Results: VPA rats have increased grooming behavior while decreased sociability (SI), social preference index (SPI), discrimination index (DI), and prepulse inhibition (PPI) compared to control. Additionally, IL-1ß, IL-6, TNF-α, and IFN-γ levels increased while IL-10 and 5-HT levels decreased in both brain regions. Astaxanthin treatment raised SI, SPI, DI, PPI, and prefrontal IL-10 levels. It also raised 5-HT levels and decreased IL-6 levels in both brain regions. Omega-3 and astaxanthin + omega-3 increased the SI, SPI, DI, and PPI and decreased grooming behavior. Moreover, they increased IL-10 and 5-HT levels whereas decreased IL-1ß, IL-6, TNF-α, IFN-γ levels in both brain regions.Conclusions: Our results showed that VPA administration mimicked the behavioral and molecular changes of autism in rats. Single and combined administration of astaxanthin and omega-3 improved the autistic-like behavioral and molecular changes in the VPA model of rats.

RESUMEN

It is well established that rats exposed to inflammation during pregnancy or the perinatal period have an increased chance of developing schizophrenia-like symptoms and behaviors, and people with schizophrenia also have raised levels of inflammatory markers. Therefore, there is evidence supporting the idea that anti-inflammatory drugs may have therapeutic benefits. Aceclofenac is a nonsteroidal anti-inflammatory drug that has anti-inflammatory properties and is used clinically to treat inflammatory and painful processes such as osteoarthritis and rheumatoid arthritis, making it a potential candidate for preventive or adjunctive therapy in schizophrenia. This study therefore examined the effect of aceclofenac in a maternal immune activation model of schizophrenia, in which polyinosinic-polycytidylic acid (Poly I:C) (8 mg/kg, i.p.) was administered to pregnant rat dams. Young female rat pups received daily aceclofenac (5, 10, and 20 mg/kg, i.p., n = 10) between postnatal day 56 and 76. The effects of aceclofenac were compared with assessment of behavioral tests and ELISA results. During the postnatal days (PNDs) 73-76, behavioral tests were conducted in rats, and on PND 76, ELISA tests were performed to examine the changes in Tumor necrosis factor alpha (TNF-α), Interleukin-1ß (IL-1ß), Brain-derived neurotrophic factor (BDNF), and nestin levels. Aceclofenac treatment reversed deficits in prepulse inhibition, novel object recognition, social interaction, and locomotor activity tests. In addition, aceclofenac administration decreased TNF-α and IL-1ß expression in the prefrontal cortex and hippocampus. In contrast, BDNF and nestin levels did not change significantly during treatment with aceclofenac. Taken together, these results suggest that aceclofenac may be an alternative therapeutic adjunctive strategy to improve the clinical expression of schizophrenia in the further studies.

Asunto(s)

Efectos Tardíos de la Exposición Prenatal , Esquizofrenia , Embarazo , Humanos , Ratas , Animales , Femenino , Esquizofrenia/inducido químicamente , Esquizofrenia/tratamiento farmacológico , Poli I-C/farmacología , Inhibidores de la Ciclooxigenasa 2 , Factor Neurotrófico Derivado del Encéfalo , Nestina , Factor de Necrosis Tumoral alfa , Modelos Animales de Enfermedad

RESUMEN

Schizophrenia is a devastating psychiatric disorder with complex symptoms and neurobiology. Serotonergic dysregulation is known to contribute to the pathogenesis of schizophrenia although dopaminergic and glutamatergic systems are thought to have central roles in neurobiology. No significant success can be achieved in the treatment of negative and cognitive symptoms while positive symptoms can be significantly reduced with current pharmacotherapy. Vortioxetine is a new multimodal antidepressant with 5-HT1A agonism, 5-HT1B partial agonism, 5-HT3, 5-HT7, and 5-HT1D antagonism, and serotonin reuptake inhibition. A limited number of studies suggest its therapeutic effect on the negative and cognitive symptoms of schizophrenia. Therefore, we investigated the potential beneficial effects of vortioxetine on behavioral and molecular deficits in the MK-801 model of schizophrenia in rats. Female Wistar albino rats (10-12 weeks) were grouped as saline, MK-801 (0.2 mg/kg), MK-801 + vortioxetine (2.5 mg/kg), MK-801 + vortioxetine (5 mg/kg), MK-801 + vortioxetine (10 mg/kg), MK-801 + risperidone (0.3 mg/kg), MK-801 + haloperidol (1 mg/kg) (n = 8 in each group). MK-801 has been daily administered (i.p.) for 14 days. Vortioxetine and antipsychotic treatments were injected for 21 days after a washout period of MK-801 and locomotor activity (LA), social interaction (SI), novel object recognition (NOR), Y-maze and prepulse inhibition (PPI) tests were performed at the 16-20th days of treatments, respectively. ELISA test was conducted to evaluate molecular analyses. MK-801 decreased PPI (%), social behaviors, and discrimination index in NOR and alternation (%) in the Y-maze test. In NOR and Y-maze tests, especially vortioxetine 5 and 10 mg/kg increased discrimination index and alternation (%) compared to MK-801. In addition, vortioxetine administration increased social behaviors. Moreover, MK-801 decreased GAD67 and parvalbumin levels while vortioxetine increased these protein levels compared to MK-801. Herein, we first suggested a potential therapeutic effect of vortioxetine, a new multimodal antidepressant, on negative and cognitive symptoms and neurobiological deficits including GAD67 and parvalbumin low expression in the MK-801 model in rats. It would be beneficial to confirm our results in different rodent models and to shed light on the possible mechanisms underlying these effects.

Asunto(s)

Maleato de Dizocilpina , Esquizofrenia , Animales , Ratas , Femenino , Vortioxetina/farmacología , Esquizofrenia/tratamiento farmacológico , Parvalbúminas , Piperazinas/farmacología , Ratas Wistar , Antidepresivos/farmacología , Agonistas del Receptor de Serotonina 5-HT1 , Cognición

RESUMEN

Diabetes mellitus (DM) is one of the globally worst killer diseases. In this study, the in vitro and in vivo antidiabetic activity and antioxidant capacity were determined and the phytochemical analyses were carried out on flower extract and sub-extracts of Rhaponticoides iconiensis. The in vitro antidiabetic activity was tested with α-amylase and α-glucosidase enzyme inhibition methods and an in vivo OGTT test in healthy and alloxan-induced rats. Although, the antioxidant activity was investigated with DPPH●, ABTS●+ and FRAP tests, the phytochemical composition analysis was carried out by LC-MS/MS. The highest α-glucosidase and α-amylase activity even from positive control acarbose were found in the ethyl acetate sub-extract of R. iconiensis (IC50 = 11.737 ± 0.823 µg/mL and 84.247 ± 0.721 µg/mL, respectively). This sub-extract also was active according to the results of in vivo tests. Moreover, the highest antioxidant activity on DPPH● (IC50 = 0.126 ± 0.002 mg/mL), FRAP (at a concentration of 1 mg/mL equivalent to 3112.052 ± 2.023 mmol Fe2+) and ABTS+● (at a concentration of 0.5 mg/mL equivalent to 0.608 ± 0.005 µM Trolox) tests. In addition, LC-MS/MS analyses of the active sub-extract revealed mainly the presence of patuletin, patuletin 3,7-diglucoside, naringin and 3,4-dicaffeoylquinic acid detected in the active sub-extract. In silico molecular docking and dynamics simulations studies were performed on these compounds with α-amylase and α-glucosidase enzymes for protein-ligand interactions and stability.