Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats
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PROVIDER: PRJNA1041888 | ENA |
REPOSITORIES: ENA
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Project description:Background: Major depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signaling during inflammation, is dysregulated in many chronic inflammatory disorders, however its role in depression and the associated sex differences have yet to be explored. Here we investigated the sex-specific antidepressant and immunomodulatory effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles. Methods: Male and female rats were treated with vehicle or DMF (25 mg/kg) while subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Hippocampal (HIP) microglial activation and alterations in gene transcripts were also evaluated. Results: DMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, however DMF treatment rescued these deficits. DMF treatment also prevented stress-induced HIP microglial activation in males. Conversely, females displayed no HIP microglial activation associated with stress exposure. Lastly, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, several differentially expressed genes in males were related to inflammatory or immune responses. Conclusions: Collectively, these findings support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression. Major depressive disorder is two times more prevalent in females than males. Further, immune system dysfunction has been shown to contribute to the development of depression, with previous studies consistently reporting chronic low-grade inflammation in depressed individuals. Not surprisingly, the immune system dysfunction associated with depression appears to be sex specific. As such, while anti-inflammatory drugs have shown antidepressant effects in preclinical studies, the sex differences in these effects are seldomly investigated. Thus, this study sought to determine the sex-specific antidepressant and immune modulatory effects of dimethyl fumarate (DMF) treatment. DMF is a drug that activates the protein nuclear factor erythroid 2-related factor 2 to initiate anti-inflammatory signaling pathways. Here, male and female rats were exposed to 8 weeks of chronic stress while receiving daily DMF treatment. Subsequently, their expression of depression- and anxiety-like behaviours, as well as learning and memory deficits were assessed. Changes in the levels of an inflammatory marker in the brain and alterations in gene expression were also evaluated. DMF treatment had antidepressant effects in male rats only but did not have anti-anxiety effects in either sex. The learning and memory deficits in both sexes were rescued with DMF treatment. Notably, chronic stress only increased inflammatory marker levels in male rats, which was prevented by DMF treatment. Additionally, DMF normalized several of the sex-specific gene alterations induced by chronic stress, with many of the male-specific genes relating to inflammatory processes. These data suggest that anti-inflammatory drugs may be an effective antidepressant treatment in males.
2023-11-21 | GSE248186 | GEO
Project description:BackgroundMajor depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signalling during inflammation, is dysregulated in many chronic inflammatory disorders; however, its role in depression and the associated sex differences have yet to be explored. Here, we investigated the sex-specific antidepressant and immunomodulatory effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles.MethodsMale and female rats were treated with vehicle or DMF (25 mg/kg) whilst subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Sex differences in hippocampal (HIP) microglial activation and gene expression response were also evaluated.ResultsDMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, and DMF treatment rescued these deficits. DMF treatment also prevented stress-induced HIP microglial activation in males. Conversely, females displayed no HIP microglial activation associated with stress exposure. Last, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, most of the differentially expressed genes in males normalized by DMF were related to antioxidant, inflammatory or immune responses.ConclusionsCollectively, these findings support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression.
| S-EPMC10863247 | biostudies-literature
Project description:Nrf2 overexpression rescues RPE morphology in mouse models of retinitis pigmentosa
| PRJNA675578 | ENA
Project description:Lung squamous cell cancer (LUSC) is associated with very poor survival due to the lack of specific treatments. A common genetic alteration in LUSC involves mutations in NFE2L2 (also named NRF2) or its regulator, KEAP1, resulting in increased activity of the NRF2 transcription factor (TF). This study compares the requirement for active-NRF2 in LUSC cell lines. Although normal-NRF2 cells are more sensitive to oxidative stress, they do not require NRF2 for survival under non-stress conditions, while LUSC cells with active-NRF2 mutations depend on NRF2 for viability. NRF2 depletion in patient-derived organoid cultures with active-NRF2 as well as in xenografts with active-NRF2 triggers cell death. A CRISPRa/dCas9 screening for gene targets capable of rescuing cell survival in these cells identified TRIM24 as a gene whose expression rescues cell survival in NRF2-depleted active-NRF2 LUSC cells. Alongside oxidative stress, the lack of TRIM24 selectively contributed to the induction of cell death (apoptosis and ferroptosis) in active-NRF2 LUSC cells. Cells with a high NFE2L2/KEAP1 copy number ratio also undergo cell death. The increase in cell death observed upon TRIM24 depletion involves a reduction in AKT activity resulting from destabilization of the PI3Ka catalytic subunit. Notably, overexpression of PI3Ka rescues cell survival in TRIM24-depleted active-NRF2 cells. These findings point to novel therapeutic approaches in LUSC.
2025-07-21 | GSE296753 | GEO
Project description:Based on the proteomics of cerebrospinal fluid (CSF), this study aimed to explore the mechanism of depression and antidepressants.
2021-09-09 | PXD021735 | Pride
Project description:Based on the proteomics of cerebrospinal fluid, this study aimed to explore the core pathway and potential targets of luteolin treatment on late-onset depression.
2023-03-11 | PXD038159 | Pride
Project description:WGS and RNA-seq data for Nrf2 study
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Project description:Nrf2 overexpression rescues RPE morphology in mouse models of retinitis pigmentosa [rd1-p20_p40_analysis]
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Project description:Nrf2 overexpression rescues RPE morphology in mouse models of retinitis pigmentosa [rd1-p20_analysis]
| PRJNA675587 | ENA
Project description:Nrf2 overexpression rescues RPE morphology in mouse models of retinitis pigmentosa [rd1-p40_analysis]
| PRJNA675588 | ENA