1. Paliperidone reverts Toll-like receptor 3 signaling pathway activation and cognitive deficits in a maternal immune activation mouse model of schizophrenia.
- Author
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MacDowell KS, Munarriz-Cuezva E, Caso JR, Madrigal JL, Zabala A, Meana JJ, García-Bueno B, and Leza JC
- Subjects
- Animals, Antioxidants pharmacology, Cognition Disorders immunology, Disease Models, Animal, Female, Frontal Lobe drug effects, Frontal Lobe immunology, Male, Memory, Short-Term drug effects, Memory, Short-Term physiology, Mice, Inbred C57BL, Poly I-C, Pregnancy, Prenatal Exposure Delayed Effects, Random Allocation, Schizophrenia immunology, Schizophrenic Psychology, Signal Transduction drug effects, Spatial Memory drug effects, Spatial Memory physiology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antipsychotic Agents pharmacology, Cognition Disorders drug therapy, Paliperidone Palmitate pharmacology, Schizophrenia drug therapy, Toll-Like Receptor 3 metabolism
- Abstract
The pathophysiology of psychotic disorders is multifactorial, including alterations in the immune system caused by exogenous or endogenous factors. Epidemiological and experimental studies indicate that infections during the gestational period represent a risk factor to develop schizophrenia (SZ) along lifetime. Here, we tested the hypothesis that the antipsychotic paliperidone regulates immune-related brain effects in an experimental model of SZ. A well described prenatal immune activation model of SZ in mice by maternal injection of the viral mimetic poly(I:C) during pregnancy was used. Young-adult offspring animals (60PND) received paliperidone ip (0.05 mg/kg) for 21 consecutive days. One day after last injection, animals were submitted to a cognitive test and brain frontal cortex (FC) samples were obtained for biochemical determinations. The adults showed an activated innate immune receptor TLR-3 signaling pathway, oxidative/nitrosative stress and accumulation of pro-inflammatory mediators such as nuclear transcription factors (i.e., NFκB) and inducible enzymes (i.e., iNOS) in FC. Chronic paliperidone blocked this neuroinflammatory response possibly by the synergic activation and preservation of endogenous antioxidant/anti-inflammatory mechanisms such as NRF2 and PPARγ pathways, respectively. Paliperidone administration also stimulated the alternative polarization of microglia to the M2 anti-inflammatory profile. In addition, paliperidone treatment improved spatial working memory deficits of this SZ-like animal model. In conclusion, chronic administration of paliperidone to young-adult mice prenatally exposed to maternal immune (MIA) challenge elicits a general preventive anti-inflammatory/antioxidant effect at both intracellular and cellular polarization (M1/M2) level in FC, as well as ameliorates specific cognitive deficits., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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