ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Prenatal Exposure Delayed Effects , Schizophrenia , Pregnancy , Humans , Rats , Animals , Female , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Poly I-C/pharmacology , Cyclooxygenase 2 Inhibitors , Brain-Derived Neurotrophic Factor , Nestin , Tumor Necrosis Factor-alpha , Disease Models, AnimalABSTRACT
RATIONALE: Maternal polyinosinic-polycytidylic acid (Poly I:C) exposure leads to an increase in various proinflammatory cytokines and causes schizophrenia-like symptoms in offspring. In recent years, group I metabotropic glutamate receptors (mGluRs) have emerged as a potential target in the pathophysiology of schizophrenia. OBJECTIVES: The aim of our study was to investigate the behavioral and molecular changes by using the mGlu1 receptor positive allosteric modulator (PAM) agent RO 67-7476, and the negative allosteric modulator (NAM) agent JNJ 16259685 and the mGlu5 receptor PAM agent VU-29, and NAM agent fenobam in the Poly I:C-induced schizophrenia model in rats. METHODS: Female Wistar albino rats were treated with Poly I:C on day 14 of gestation after mating. On the postnatal day (PND) 34-35, 56-57 and 83-84, behavioral tests were performed in the male offspring. On the PND84, brain tissue was collected and the level of proinflammatory cytokines was determined by ELISA method. RESULTS: Poly I:C caused impairments in all behavioral tests and increased the levels of proinflammatory cytokines. While PAM agents caused significant improvements in prepulse inhibition (PPI), novel object recognition (NOR), spontaneous alternation and reference memory tests, they brought the levels of proinflammatory cytokines closer to the control group. NAM agents were ineffective on behavioral tests. It was observed that PAM agents significantly improved Poly I:C-induced disruption in behavioral and molecular analyses. CONCLUSIONS: These results suggest that PAM agents, particularly the mGlu5 receptor VU-29, are also promising and could be a potential target in schizophrenia.
