The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

• Published in: Neurotherapeutics Vol. 13; no. 4; pp. 833 - 843
• Main Authors: MacDowell, Karina S., Caso, Javier R., Martín-Hernández, David, Moreno, Beatriz M., Madrigal, José L. M., Micó, Juan A., Leza, Juan C., García-Bueno, Borja
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2016; Springer Nature B.V
• Subjects: Aldehydes - metabolism; Analysis of Variance; Animals; Antioxidants; Antioxidants - metabolism; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Antipsychotics; Biomedical and Life Sciences; Biomedicine; Brain; Catalase - genetics; Catalase - metabolism; Chronic illnesses; Cytokines; Cytokines - genetics; Cytokines - metabolism; Disease Models, Animal; Enzymes; Growth factors; Immune system; Inflammation; Kinases; Male; Neurobiology; Neurology; Neurosciences; Neurosurgery; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Original; Original Article; Paliperidone Palmitate - pharmacology; Paliperidone Palmitate - therapeutic use; Proteins; Psychotropic drugs; Rats; Rats, Wistar; Restraint, Physical - adverse effects; RNA, Messenger - metabolism; Signal Transduction - drug effects; Stress; Stress, Psychological - drug therapy; Stress, Psychological - etiology; Superoxide Dismutase - metabolism; Time Factors; Transcription factors; Up-Regulation - drug effects; Vitamin B; Borja Spain; Madrid Spain; Spain; Antipsychotics; Restraint stress; M2 microglia; NRF2; Antioxidant enzymes; IL-10
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-016-0438-2

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.