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 stressinduced 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.

Anti-stress Properties of Atypical Antipsychotics

“…In more detail, chronic administration of lurasidone for 5 weeks can counteract the CMS-induced increase of the pro-oxidant enzyme NADPH oxidase 2 (NOX2) levels as well as the reduced levels of antioxidant mediator nuclear factor erythroid 2-related factor 2 (NRF2) in the dorsal hippocampus [ 38 ]. These results are in line with another report showing that chronic administration of paliperidone regulates the redox machinery by counteracting the reduction of NRF2 in the prefrontal cortex of rats exposed to chronic restraint stress [ 143 ].…”

Chronic Stress Exposure Reduces Parvalbumin Expression in the Rat Hippocampus through an Imbalance of Redox Mechanisms: Restorative Effect of the Antipsychotic Lurasidone

“…Interestingly, similar mechanisms have also been described for other psychotropic drugs, including antidepressants (Martín-Hernández et al, 2016; Omar and Tash, 2017) and antipsychotics (MacDowell et al, 2016). It is interesting to note that the modulation of NRF2 and KEAP1 showed a significant Pearson correlation (positive and negative, respectively) with PVB protein levels, providing further support to the notion that the alterations of the GABAergic system following CMS exposure may be causally linked to a dysregulation of the oxidative balance in the D-HIP.…”

Association between medication adherence and oxidative stress in patients with first-episode mania

“…Conflicting results have been obtained in a variety of studies on the antioxidant effect of treatments based on typical and atypical antipsychotics and lithium, and how they regulate oxidative stress in preclinical studies (18,19,(35)(36)(37)(38)(39). In our study, an increase in oxidative stress levels and a decrease in antioxidant response were noted in the two groups at 6 months, regardless of the medication administered.…”

“…In relation to antipsychotic drugs-one of the most powerful drugs for acute manic episodes (16)-, there is evidence that risperidone has an antioxidant effect (17). In animal models, paliperidone has been observed to regulate endogenous antioxidant pathways by preventing a decrease in antioxidant levels (18) or inducing its increase (19).…”