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Dimethyl Fumarate Protects Brain From Damage Produced by Intracerebral Hemorrhage by Mechanism Involving Nrf2.

ABSTRACT: Intracerebral hemorrhage (ICH) represents a devastating form of stroke for which there is no effective treatment. This preclinical study was designed to evaluate dimethyl fumarate (DMF), a substance recently approved for the treatment of multiple sclerosis, as therapy for ICH. We hypothesized that DMF through activating the master regulator of cellular self-defense responses, transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), would act as effective treatment for ICH-mediated damage.Male rats and mice, including Nrf2 knockouts, were subjected to intracerebral injection of blood (to mimic ICH) and then treated with DMF. Neurological deficit, brain edema, gene induction profile and hematoma resolution were evaluated. Phagocytic functions of primary microglia in culture were used to study hematoma resolution.Treatment with DMF induced Nrf2-target genes, improved hematoma resolution, reduced brain edema, and ultimately enhanced neurological recovery in rats and wild-type, but not Nrf2 knockout, mice. Most importantly, the treatment of ICH with DMF showed a 24 h window of therapeutic opportunity.A clinically relevant dose of DMF demonstrates potent therapeutic efficacy and impressive 24 h therapeutic window of opportunity. This study merits further evaluation of this compound as potential treatment for ICH in humans.

SUBMITTER: Zhao X

PROVIDER: S-EPMC4480061 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Dimethyl Fumarate Protects Brain From Damage Produced by Intracerebral Hemorrhage by Mechanism Involving Nrf2.

Zhao Xiurong X Sun Guanghua G Zhang Jie J Ting Shun-Ming SM Gonzales Nicole N Aronowski Jaroslaw J

Stroke 20150514 7

<h4>Background and purpose</h4>Intracerebral hemorrhage (ICH) represents a devastating form of stroke for which there is no effective treatment. This preclinical study was designed to evaluate dimethyl fumarate (DMF), a substance recently approved for the treatment of multiple sclerosis, as therapy for ICH. We hypothesized that DMF through activating the master regulator of cellular self-defense responses, transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), would act as effe ...[more]

PMID: 25977275

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Project description:Background and purposeEdema formation, inflammation and increased blood-brain barrier permeability contribute to poor outcomes after intracerebral hemorrhage (ICH). This study examined the therapeutic effect of dimethyl fumarate (DMF), a fumaric acid ester that activates nuclear factor erythroid-2 related factor 2 (Nrf2) and Nrf2 heterodimerization effector protein musculo-aponeurotic fibrosarcoma-G (MAFG) in a murine ICH model.MethodsMale CD-1 mice (n=176) were subjected to intrastriatal infusion of bacterial collagenase (n=126), autologous blood (n=18) or sham surgery (n=32). Four (4) animals not subjected to ICH (naive) were also included in the study. After ICH, animals either received vehicle, dimethyl fumarate (10 mg or 100 mg/kg) or casein kinase 2 inhibitor (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid (TBCA). Thirty-two mice also received scrambled siRNA or MAFG siRNA 24h before ICH. Brain water content and neurological function were evaluated.ResultsDimethyl fumarate reduced Evans blue dye extravasation, decreased brain water content, and improved neurological deficits at 24 and 72 h after ICH. Casein kinase 2 inhibitor TBCA and MAFG siRNA prevented the effect of dimethyl fumarate on brain edema and neurological function. After ICH, ICAM-1 levels increased and casein kinase 2 levels decreased. Dimethyl fumarate reduced ICAM-1 but enhanced casein kinase 2 levels. Again, casein kinase 2 inhibitor TBCA and MAFG siRNA abolished the effect of dimethyl fumarate on ICAM-1 and casein kinase 2. Dimethyl fumarate preserved pNrf2 and MAFG expression in the nuclear lysate after ICH and the effect of dimethyl fumarate was abolished by casein kinase 2 inhibitor TBCA and MAFG siRNA. Dimethyl fumarate reduced microglia activation in peri-hematoma areas after ICH. The protective effect of dimethyl fumarate on brain edema and neurological function was also observed in a blood injection mouse model.ConclusionDimethyl fumarate ameliorated inflammation, reduced blood-brain barrier permeability, and improved neurological outcomes by casein kinase 2 and Nrf2 signaling pathways after experimental ICH in mice.

Project description:Intracerebral hemorrhage (ICH) is a subtype of stroke involving formation of hematoma within brain parenchyma, which accounts for 8-15% of all strokes in Western societies and 20-30% among Asian populations, and has a 1-year mortality rate >50%. The high mortality and severe morbidity make ICH a major public health problem. Only a few evidence-based targeted treatments are used for ICH management, and interventions focus primarily on supportive care and comorbidity prevention. Even in patients who survive the ictus, extravasated blood (including plasma components) and subsequent intrahematoma hemolytic products trigger a series of adverse events within the brain parenchyma, leading to secondary brain injury, edema and severe neurological deficits or death. Although the hematoma in humans gradually resolves within months, full restoration of neurological function can be slow and often incomplete, leaving survivors with devastating neurological deficits. During past years, peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor and its agonists received recognition as important players in regulating not only glucose and lipid metabolism (which underlies its therapeutic effect in type 2 diabetes mellitus), and more recently, as an instrumental pleiotropic regulator of antiinflammation, antioxidative regulation, and phagocyte-mediated cleanup processes. PPARγ agonists have emerged as potential therapeutic target for stroke. The use of PPARγ as a therapeutic target appears to have particularly strong compatibility toward pathogenic components of ICH. In addition to its direct genomic effect, PPARγ may interact with transcription factor, NF-κB, which may underlie many aspects of the antiinflammatory effect of PPARγ. Furthermore, PPARγ appears to regulate expression of Nrf2, another transcription factor and master regulator of detoxification and antioxidative regulation. Finally, the synergistic costimulation of PPARγ and retinoid X receptor, RXR, may play an additional role in the therapeutic modulation of PPARγ function. In this article, we outline the main components of the role of PPARγ in ICH pathogenesis.

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Dimethyl Fumarate Protects Brain From Damage Produced by Intracerebral Hemorrhage by Mechanism Involving Nrf2.

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Dimethyl Fumarate Protects Brain From Damage Produced by Intracerebral Hemorrhage by Mechanism Involving Nrf2.

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