title: Paliperidone reverts Toll-like receptor 3 signaling pathway activation and cognitive deficits in a maternal immune activation mouse model of schizophrenia.
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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, Madrid, Spain; Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre & IUINQ, Madrid, Spain.
authors.forename: Karina S
authors.initials: KS
authors.lastname: MacDowell
authors.affiliation: Department of Pharmacology, University of Basque Country UPV/EHU, Bizkaia, Spain; Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Munarriz-Cuezva
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, Madrid, Spain; Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre & IUINQ, Madrid, Spain.
authors.forename: Javier R
authors.initials: JR
authors.lastname: Caso
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, Madrid, Spain; Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre & IUINQ, Madrid, Spain.
authors.forename: José L M
authors.initials: JL
authors.lastname: Madrigal
authors.affiliation: Department of Neurosciences, University of Basque Country UPV/EHU, Bizkaia, Spain; Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Spain; BioCruces Health Research Institute, Bizkaia, Spain.
authors.forename: Arantzazu
authors.initials: A
authors.lastname: Zabala
authors.affiliation: Department of Pharmacology, University of Basque Country UPV/EHU, Bizkaia, Spain; Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Spain; BioCruces Health Research Institute, Bizkaia, Spain.
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, Madrid, Spain; Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre & IUINQ, Madrid, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: García-Bueno
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, Madrid, Spain; Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre & IUINQ, Madrid, Spain. Electronic address: jcleza@med.ucm.es.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Leza
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000276:immunology; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D000068882:Paliperidone Palmitate / Q000494:pharmacology*; D011070:Poly I-C; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D012559:Schizophrenia / Q000188:drug therapy* / Q000276:immunology; D012565:Schizophrenic Psychology; D015398:Signal Transduction / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D014150:Antipsychotic Agents; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011070:Poly I-C; D000068882:Paliperidone Palmitate
keywords: Inflammation; Maternal immune activation; Paliperidone; TLR3