fumarates and Brain-Edema

Oxidative stress plays an important role in cerebral ischemia-reperfusion injury. Dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) are antioxidant agents that can activate the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and induce the expression of antioxidant proteins. Here, we evaluated the impact of DMF and MMF on ischemia-induced brain injury and whether the Nrf2 pathway mediates the effects provided by DMF and MMF in cerebral ischemia-reperfusion injury. Using a mouse model of transient focal brain ischemia, we show that DMF and MMF significantly reduce neurological deficits, infarct volume, brain edema, and cell death. Further, DMF and MMF suppress glial activation following brain ischemia. Importantly, the protection of DMF and MMF was mostly evident during the subacute stage and was abolished in Nrf2

Topics: Animals; Brain Edema; Calcium-Binding Proteins; Dimethyl Fumarate; Disease Models, Animal; Dose-Response Relationship, Drug; Fumarates; Glial Fibrillary Acidic Protein; Glutathione; Immunosuppressive Agents; Infarction, Middle Cerebral Artery; Maleates; Malondialdehyde; Mice; Mice, Inbred C57BL; Microfilament Proteins; Neurologic Examination; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Recovery of Function; Reperfusion Injury; Time Factors

Brain edema is a hallmark of various neuropathologies, but the underlying mechanisms are poorly understood. We aim to characterize how tissue hypoxia, together with oxidative stress and inflammation, leads to capillary dysfunction and breakdown of the blood-brain barrier (BBB). In a mouse stroke model we show that systemic treatment with dimethyl fumarate (DMF), an antioxidant drug clinically used for psoriasis and multiple sclerosis, significantly prevented edema formation in vivo. Indeed, DMF stabilized the BBB by preventing disruption of interendothelial tight junctions and gap formation, and decreased matrix metalloproteinase activity in brain tissue. In vitro, DMF directly sustained endothelial tight junctions, inhibited inflammatory cytokine expression, and attenuated leukocyte transmigration. We also demonstrate that these effects are mediated via activation of the redox sensitive transcription factor NF-E2 related factor 2 (Nrf2). DMF activated the Nrf2 pathway as shown by up-regulation of several Nrf2 target genes in the brain in vivo, as well as in cerebral endothelial cells and astrocytes in vitro, where DMF also increased protein abundance of nuclear Nrf2. Finally, Nrf2 knockdown in endothelial cells aggravated subcellular delocalization of tight junction proteins during ischemic conditions, and attenuated the protective effect exerted by DMF. Overall, our data suggest that DMF protects from cerebral edema formation during ischemic stroke by targeting interendothelial junctions in an Nrf2-dependent manner, and provide the basis for a completely new approach to treat brain edema.

Topics: Animals; Animals, Newborn; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Cell Movement; Dimethyl Fumarate; Fumarates; Immunosuppressive Agents; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; RNA, Small Interfering; Stroke; Tight Junctions