title: The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress.
abstract: Alterations in the innate inflammatory response may underlie the pathophysiology of psychiatric diseases. Current antipsychotics modulate pro-/anti-inflammatory pathways, but their specific actions on these pathways remain only partly explored. This study was conducted to elucidate the regulatory role of paliperidone (1 mg/kg i.p.) on acute (6 h) and chronic (6 h/day for 21 consecutive days) restraint stress-induced alterations in 2 emerging endogenous anti-inflammatory/antioxidant mechanisms: nuclear factor erythroid-related factor 2 (NRF2)/antioxidant enzymes pathway, and the cytokine milieu regulating M1/M2 polarization in microglia, analyzed at the mRNA and protein levels in prefrontal cortex samples. In acute stress conditions, paliperidone enhanced NRF2 levels, possibly related to phosphoinositide 3-kinase upregulation and reduced kelch-Like ECH-associated protein 1 expression. In chronic conditions, paliperidone tended to normalize NRF2 levels through a phosphoinositide 3-kinase related-mechanism, with no effects on kelch-Like ECH-associated protein 1. Antioxidant response element-dependent antioxidant enzymes were upregulated by paliperidone in acute stress, while in chronic stress, paliperidone tended to prevent stress-induced downregulation of the endogenous antioxidant machinery. However, paliperidone increased transforming growth factor-β and interleukin-10 in favor of an M2 microglia profile in acute stress conditions, which was also corroborated by paliperidone-induced increased levels of the M2 cellular markers arginase I and folate receptor 2. This latter effect was also produced in chronic conditions. Immunofluorescence studies suggested an increase in the number of microglial cells expressing arginase I and folate receptor 2 in the stressed animals pretreated with paliperidone. In conclusion, the enhancement of endogenous antioxidant/anti-inflammatory pathways by current and new antipsychotics could represent an interesting therapeutic strategy for the future.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, 28040, Madrid, Spain.|Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM, Madrid, Spain.
authors.forename: Karina S
authors.initials: KS
authors.lastname: MacDowell
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, 28040, Madrid, Spain.|Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM, Madrid, Spain.|Department of Psychiatry, Faculty of Medicine, University Complutense, 28040, Madrid, Spain.
authors.forename: Javier R
authors.initials: JR
authors.lastname: Caso
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, 28040, Madrid, Spain.|Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Martín-Hernández
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, 28040, Madrid, Spain.|Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM, Madrid, Spain.
authors.forename: Beatriz M
authors.initials: BM
authors.lastname: Moreno
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, 28040, Madrid, Spain.|Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM, Madrid, Spain.
authors.forename: José L M
authors.initials: JLM
authors.lastname: Madrigal
authors.affiliation: Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain.|Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Micó
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, 28040, Madrid, Spain.|Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM, Madrid, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Leza
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, 28040, Madrid, Spain. bgbueno@med.ucm.es.|Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain. bgbueno@med.ucm.es.|Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM, Madrid, Spain. bgbueno@med.ucm.es.
authors.forename: Borja
authors.initials: B
authors.lastname: García-Bueno
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D000068882:Paliperidone Palmitate / Q000494:pharmacology* / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects*; D013315:Stress, Psychological / Q000188:drug therapy* / Q000209:etiology; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D014150:Antipsychotic Agents; D016207:Cytokines; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D002374:Catalase; D013482:Superoxide Dismutase; C027576:4-hydroxy-2-nonenal; D000068882:Paliperidone Palmitate
keywords: Antioxidant enzymes; Antipsychotics; IL-10; M2 microglia; NRF2; Restraint stress