Dimethyl fumarate for ischemic stroke

In a series of proof-of-concept experiments using in vitro and in vivo models of ischemic stroke, we provide evidence that dimethyl fumarate (DMF) strongly reduces neuronal cell death upon ischemic insult through pleiotropic anti-inflammatory and cytoprotective effects [1, 2]. DMF is a derivative of the fumaric acid, an intermediate product of the citric acid cycle. DMF is marketed as Tecfidera ® (formerly known as BG-12; Biogen, USA), and is used as a peroral treatment for relapsing-remitting multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS) [3]. Notably, MS and ischemic stroke share several pathophysiological mechanisms including oxidative stress, and recruitment and pro-inflammatory activation of resident and circulating immunocompetent cells. In mice suffering from focal ischemic stroke, orally administered DMF clearly reduced the development of vasogenic edema by maintaining the integrity of interendothelial tight junctions (TJ) which form a physical barrier restricting the paracellular influx of blood-derived molecules and fluid into the CNS [1]. We further demonstrated that DMF diminished the pro-inflammatory activation of astrocytes and brain microvascular endothelial cells in response to ischemic stress in vitro and suppressed monocyte migration across a brain endothelial cell monolayer presumably by downregulation of leukocyte adhesion molecules [1]. Using murine organotypic hippocampal slice cultures and neuronal cell lines subjected to ischemia-reoxygenation in vitro, we then showed that DMF ameliorates neuronal viability also through direct cytoprotective actions independent of its effects on non-neuronal brain cells [2]. Pharmacokinetic studies in human volunteers indicate that orally applied DMF is rapidly cleaved in the alkaline environment of the intestine into monomethyl fumarate (MMF) by esterases, and additionally undergoes a strong first-pass effect in the liver. Thus, MMF as the main metabolite is considered the active compound in the body [3]. Hence, we compared the neuroprotective potential of both fumaric acid esters (FAE), and confirmed equal ischemic tolerance of neurons treated either with DMF or MMF [2]. Although the exact mechanism of action of DMF in MS patients is still unclear, a number of experimental animal studies have provided important insights into molecular mechanisms which might underlie the favorable effects of oral DMF [4-7]. FAE are electrophiles and serve as " Michael acceptors " that covalently link to nucleophilic thiol groups on macromolecules, as it has been shown for reactive cysteine residues of the Kelch-like ECH-associated protein 1 (Keap1) [4, 5]. Keap1 acts as an inhibitor of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a major …