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Treatment with dimethyl fumarate reduces the formation and rupture of intracranial aneurysms: Role of Nrf2 activation.

ABSTRACT: Oxidative stress and chronic inflammation in arterial walls have been implicated in intracranial aneurysm (IA) formation and rupture. Dimethyl fumarate (DMF) exhibits immunomodulatory properties, partly via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway which reduces oxidative stress by inducing the antioxidant response element (ARE). This study evaluated the effects of DMF both in vitro, using tumor necrosis factor (TNF)-α-treated vascular smooth muscle cells (VSMC), and in vivo, using a murine elastase model to induce aneurysm formation. The mice were treated with either DMF at 100 mg/kg/day P.O. or vehicle for two weeks. DMF treatment protected VSMCs from TNF-α-induced inflammation as demonstrated by its downregulation of cytokines and upregulation of Nrf2 and smooth muscle cell markers. At higher doses, DMF also inhibited the pro-proliferative action of TNF-α by increasing apoptosis which protected the cells from aponecrosis. In mice, DMF treatment significantly decreased the incidence of aneurysm formation and rupture, at the same time increasing Nrf2 levels. DMF demonstrated a neuroprotective effect in mice with a resultant inhibition of oxidative stress, inflammation, and fibrosis in the cerebrovasculature. This suggests a potential role for DMF as a rescue therapy for patients at risk for formation and rupture of IAs.

SUBMITTER: Pascale CL

PROVIDER: S-EPMC7181091 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Treatment with dimethyl fumarate reduces the formation and rupture of intracranial aneurysms: Role of Nrf2 activation.

Pascale Crissey L CL Martinez Alejandra N AN Carr Christopher C Sawyer David M DM Ribeiro-Alves Marcelo M Chen Mimi M O'Donnell Devon B DB Guidry Jessie J JJ Amenta Peter S PS Dumont Aaron S AS

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20190620 5

Oxidative stress and chronic inflammation in arterial walls have been implicated in intracranial aneurysm (IA) formation and rupture. Dimethyl fumarate (DMF) exhibits immunomodulatory properties, partly via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway which reduces oxidative stress by inducing the antioxidant response element (ARE). This study evaluated the effects of DMF both in vitro, using tumor necrosis factor (TNF)-α-treated vascular smooth muscle cells (VSMC ...[more]

PMID: 31220996

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Project description:BackgroundCerebral malaria (CM) is associated with morbidity and mortality despite the use of potent anti-malarial agents. Brain endothelial cell activation and dysfunction from oxidative and inflammatory host responses and products released by Plasmodium falciparum-infected erythrocytes (IE), are likely the major contributors to the encephalopathy, seizures, and brain swelling that are associated with CM. The development of adjunctive therapy to reduce the pathological consequences of host response pathways could improve outcomes. A potentially protective role of the nuclear factor E2-related factor 2 (NRF2) pathway, which serves as a therapeutic target in brain microvascular diseases and central nervous system (CNS) inflammatory diseases such as multiple sclerosis was tested to protect endothelial cells in an in vitro culture system subjected to tumour necrosis factor (TNF) or infected red blood cell exposure. NRF2 is a transcription factor that mediates anti-oxidant and anti-inflammatory responses.MethodsTo accurately reflect clinically relevant parasite biology a unique panel of parasite isolates derived from patients with stringently defined CM was developed. The effect of TNF and these parasite lines on primary human brain microvascular endothelial cell (HBMVEC) activation in an in vitro co-culture model was tested. HBMVEC activation was measured by cellular release of IL6 and nuclear translocation of NFκB. The transcriptional and functional effects of dimethyl fumarate (DMF), an FDA approved drug which induces the NRF2 pathway, on host and parasite induced HBMVEC activation was characterized. In addition, the effect of DMF on parasite binding to TNF stimulated HBMVEC in a semi-static binding assay was examined.ResultsTranscriptional profiling demonstrates that DMF upregulates the NRF2-Mediated Oxidative Stress Response, ErbB4 Signaling Pathway, Peroxisome Proliferator-activated Receptor (PPAR) Signaling and downregulates iNOS Signaling and the Neuroinflammation Signaling Pathway on TNF activated HBMVEC. The parasite lines derived from eight paediatric CM patients demonstrated increased binding to TNF activated HBMVEC and varied in their binding and activation of HBMVEC. Overall DMF reduced both TNF and CM derived parasite activation of HBMVEC.ConclusionsThese findings provide evidence that targeting the NRF2 pathway in TNF and parasite activated HBMVEC mediates multiple protective pathways and may represent a novel adjunctive therapy to improve infection outcomes in CM.

Project description:Dimethyl fumarate (DMF) is pharmaceutical activator of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates of many cellular antioxidant response pathways, and has been used to treat inflammatory diseases such as multiple sclerosis. However, DMF has been shown to produce adverse effects on offspring in animal studies and as such is not recommended for use during pregnancy. The goal of this work is to better understand how these adverse effects are initiated and the role of DMF-induced Nrf2 activation during three critical windows of development in embryonic zebrafish (Danio rerio): pharyngula, hatching, and protruding-mouth stages. To evaluate Nrf2 activation, wildtype zebrafish, and mutant zebrafish (nrf2afh318/fh318) embryos with a loss of function mutation in Nrf2a, the co-ortholog to human Nrf2, were treated for 6 h with DMF (0-20 μM) beginning at the pharyngula, hatching, or protruding-mouth stage and assessed for survival and morphology. Nrf2a mutant fish had an increase in survival, however, morphology studies demonstrated Nrf2a mutant fish had more severe deformities occurring with exposures during the hatching stage. To verify Nrf2 cellular localization and downstream impacts on protein-S-glutathionylation in situ, a concentration below the LOAEL was chosen (7 μM) for immunohistochemistry and S-glutathionylation. Embryos were imaged via epifluorescence microscopy studies, the Nrf2a protein in the body tissue was decreased with DMF only when exposed at the hatching stage, while total protein S-glutathionylation was modulated by Nrf2a activity and DMF during the pharyngula and protruding-mouth stage. The pancreatic islet and liver were further analyzed via confocal microscopy. Pancreatic islets and liver also had tissue specific differences with Nrf2a protein expression and protein S-glutathionylation. This work demonstrates how critical windows of exposure and Nrf2a activity may influence toxicity of DMF and highlights tissue-specific changes in Nrf2a protein levels and S-glutathionylation in pancreatic islet and liver during embryonic development.

Project description:BACKGROUND AND PURPOSE:Many ruptured intracranial aneurysms (IAs) are small. Clinical presentations suggest that small and large IAs could have different phenotypes. It is unknown if small and large IAs have different characteristics that discriminate rupture. METHODS:We analyzed morphological, hemodynamic, and clinical parameters of 413 retrospectively collected IAs (training cohort; 102 ruptured IAs). Hierarchal cluster analysis was performed to determine a size cutoff to dichotomize the IA population into small and large IAs. We applied multivariate logistic regression to build rupture discrimination models for small IAs, large IAs, and an aggregation of all IAs. We validated the ability of these 3 models to predict rupture status in a second, independently collected cohort of 129 IAs (testing cohort; 14 ruptured IAs). RESULTS:Hierarchal cluster analysis in the training cohort confirmed that small and large IAs are best separated at 5 mm based on morphological and hemodynamic features (area under the curve=0.81). For small IAs (<5 mm), the resulting rupture discrimination model included undulation index, oscillatory shear index, previous subarachnoid hemorrhage, and absence of multiple IAs (area under the curve=0.84; 95% confidence interval, 0.78-0.88), whereas for large IAs (≥5 mm), the model included undulation index, low wall shear stress, previous subarachnoid hemorrhage, and IA location (area under the curve=0.87; 95% confidence interval, 0.82-0.93). The model for the aggregated training cohort retained all the parameters in the size-dichotomized models. Results in the testing cohort showed that the size-dichotomized rupture discrimination model had higher sensitivity (64% versus 29%) and accuracy (77% versus 74%), marginally higher area under the curve (0.75; 95% confidence interval, 0.61-0.88 versus 0.67; 95% confidence interval, 0.52-0.82), and similar specificity (78% versus 80%) compared with the aggregate-based model. CONCLUSIONS:Small (<5 mm) and large (≥5 mm) IAs have different hemodynamic and clinical, but not morphological, rupture discriminants. Size-dichotomized rupture discrimination models performed better than the aggregate model.

Dataset Information

Treatment with dimethyl fumarate reduces the formation and rupture of intracranial aneurysms: Role of Nrf2 activation.

Publications

Treatment with dimethyl fumarate reduces the formation and rupture of intracranial aneurysms: Role of Nrf2 activation.

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