Mac-Dowell Mata, Karina SoledadCaso Fernández, Javier RubénDavid Martín-HernándezBeatriz M. MorenoJosé L. M. MadrigalMuñoz Madrigal, José LuisJuan A. MicóLeza Cerro, Juan CarlosGarcía Bueno, Borja2026-03-242026-03-242016-04-27MacDowell KS, Caso JR, Martín-Hernández D, Moreno BM, Madrigal JLM, Micó JA, Leza JC, García-Bueno B. The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress. Neurotherapeutics. 2016 Oct;13(4):833-843. doi: 10.1007/s13311-016-0438-2. PMID: 27233514; PMCID: PMC5081131.10.1007/s13311-016-0438-2https://hdl.handle.net/20.500.14352/134269Alterations 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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articlehttps://doi.org/10.1007/s13311-016-0438-2https://www.sciencedirect.com/science/article/pii/S187874792301499X?via%3Dihubopen access616.895.8Antioxidant enzymesAntipsychoticsIL-10; M2 microgliaNRF2Restraint stressCiencias Biomédicas32 Ciencias Médicas