Alterations in the Nrf2–Keap1 signaling pathway and its downstream target genes in rat brain under stress

Djordjević, Jelena; Djordjević, Ana; Adžić, Miroslav; Mitić, Miloš; Lukić, Iva; Radojčić, Marija B.

doi:10.1016/j.brainres.2015.01.010

Cited by 55 publications

(28 citation statements)

References 59 publications

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“…We found high levels of anxiety and social avoidance in BXD84/RwwJ RI mice (low Nrf2 expressing mice at PND 21) (Fig. 1 and 3), it is in agreement with other studies, which also indicated a possible role of Nrf2, especially a decrease in Nrf2 levels in male rats, in pathogenesis of anxiety disorders (Djordjevic et al, 2015; Khalifeh et al, 2015). Other studies reported that anxiety levels are linked to the oxidative status through the central and peripheral systems in male mice (Rammal et al, 2008).…”

Section: Discussionsupporting

confidence: 92%

“…The results in the BXD84/RwwJ RI strain, which is implicated in anxiety disorder and social avoidance-like behavior corroborate earlier observations. It has been previously suggested that oxidative stress causes anxiety-related behaviors (Bouayed et al, 2009; Djordjevic et al, 2015; Hovatta et al, 2005; Khalifeh et al, 2015; Rammal et al, 2008). The first study, which identified a close relationship between oxidative stress and anxiety disorders, used six inbred male mouse strains showing that A/J, DBA/2J and 129S6/SvEvTac were the most anxious and FVB/NJ the least anxious strains (Hovatta et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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BXD recombinant inbred strains participate in social preference, anxiety and depression behaviors along sex-differences in cytokines and tactile allodynia

López-Granero

Santos

Ferrer

et al. 2017

Psychoneuroendocrinology

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Depression and anxiety are the most common psychiatric disorders, representing a major public health concern. Dysregulation of oxidative and inflammatory systems may be associated with psychiatric disorders, such as depression and anxiety. Due to the need to find appropriate animal models to the understanding of such disorders, we queried whether 2 BXD recombinant inbred (RI) mice strains (BXD21/TyJ RI and BXD84/RwwJ RI mice) and C57BL/6 wild-type mice show differential performance in depression and anxiety related behaviors and biomarkers. Specifically, we assessed forced swim, elevated plus maze, social preference and Von Frey tests at 3-4 months-of-age, as well as activation of cytokines and antioxidant mRNA levels in the cortex at 7 months-of-age. We report that (1) the BXD84/RwwJ RI strain exhibits anxiety disorder and social avoidance-like behavior (2) BXD21/TyJ RI strain show a resistance to depression illness, and (3) sex-dependent cytokine profiles and allodynia with elevated inflammatory activity were inherent to male BXD21/TyJ RI mice. In conclusion, we provide novel data in favor of the use of BXD recombinant inbred mice to further understand anxiety and depression disorders.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

BXD recombinant inbred strains participate in social preference, anxiety and depression behaviors along sex-differences in cytokines and tactile allodynia

López-Granero

Santos

Ferrer

et al. 2017

Psychoneuroendocrinology

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“…Our results showing no increase in SOD, CAT and GRx activities (Nrf2 target genes) at least at the time points studied here are still in line with the pattern of ROS and GSSG detoxification, but argue against antioxidant enzyme regulation by Nrf2 (Bataille and Manautou 2012; Djordjevic et al 2015). These observations could be explained considering that transcriptional regulation by nuclear receptors is a complex mechanism involving not only activation by an agonist, but also the interplay of coactivators and corepressors that leads to an agonist-, cell type- and promoter-specific regulation.…”

Section: Discussionsupporting

confidence: 72%

The trypanocidal benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2)

Rigalli

Perdomo

Ciriaci

et al. 2016

Toxicology and Applied Pharmacology

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Oxidative stress is a frequent cause underlying drug-induced hepatotoxicity. Benznidazole (BZL) is the only antitripanocide agent available for treatment of Chagas disease in endemic areas. Its use is associated with side effects, including increases in biomarkers of hepatotoxicity. However, BZL potential to cause oxidative stress has been poorly investigated. Here, we evaluated the effect of a pharmacologically relevant BZL concentration (200 μM) at different time points on redox status and the counteracting mechanisms in the human hepatic cell line HepG2. BZL increased reactive oxygen species (ROS) after 1 and 3 h of exposure, returning to normality at 24 h. Additionally, BZL increased glutathione peroxidase activity at 12 h and the oxidized glutathione/total glutathione (GSSG/GSSG+GSH) ratio that reached a peak at 24 h. Thus, an enhanced detoxification of peroxide and GSSG formation could account for ROS normalization. GSSG/GSSG+GSH returned to control values at 48 h. Expression of the multidrug resistance-associated protein 2 (MRP2) and GSSG efflux via MRP2 were induced by BZL at 24 and 48 h, explaining normalization of GSSG/GSSG+GSH. BZL activated the nuclear erythroid 2-related factor 2 (Nrf2), already shown to modulate MRP2 expression in response to oxidative stress. Nrf2 participation was confirmed using Nrf2-knockout mice in which MRP2 mRNA expression was not affected by BZL. In summary, we demonstrated a ROS increase by BZL in HepG2 cells and a glutathione peroxidase- and MRP2 driven counteracting mechanism, being Nrf2 a key modulator of this response. Our results could explain hepatic alterations associated with BZL therapy.

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“…2). As it has been described in previous pathological scenarios, stress protocols included In the particular cases, ArgI localizes to the respective cellular marker with areas of overlap appearing yellow/orange in the merged image (white arrows) Scale bar = 50 μm [33], KEAP1 sequesters NRF2 in the cytoplasm, leading to ubiquitination and subsequent degradation by the 26S proteasome [34]. When cells are exposed to oxidative/nitrosative stress challenges, NRF2 escapes KEAP1-mediated repression and translocates to the nucleus activating ARE-dependent antioxidant enzymes [35].…”

Section: Discussionmentioning

confidence: 91%

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

et al. 2016

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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.

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Alterations in the Nrf2–Keap1 signaling pathway and its downstream target genes in rat brain under stress

Cited by 55 publications

References 59 publications

BXD recombinant inbred strains participate in social preference, anxiety and depression behaviors along sex-differences in cytokines and tactile allodynia

BXD recombinant inbred strains participate in social preference, anxiety and depression behaviors along sex-differences in cytokines and tactile allodynia

The trypanocidal benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2)

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

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