Dimethyl Fumarate Confers Neuroprotection through CK2 Mediated Phosphorylation of Nrf2 in Murine Intracerebral Hemorrhage

Abstract

Background and purpose Edema formation and inflammation contribute to poor outcomes after intracerebral hemorrhage (ICH). This study examined the effect of Dimethyl fumarate (DMF) on brain water content, neurological outcomes and inflammation after ICH. We also evaluated the role of casein kinase 2 phosphorylation of Nrf2 and musculo-aponeurotic fibrosacoma-G (MAF-G) in DMF mediated neuroprotection. Methods: Male CD-1 mice (n=114) were subjected to intrastriatal infusion of bacterial collagenase (n=72), autologous blood injection (n=18) or sham surgery (n=24). After ICH, animals received vehicle, 10mg or 100mg/kg DMF, casein kinase 2 (CK2) inhibitor (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid (TBCA). Twenty-four mice also received control siRNA musculo-aponeurotic fibrosacoma-G (MAFG) siRNA 24 hours before ICH. Results: Treatment with DMF reduced brain water content and improved neurological deficits at 24 and 72 hours after ICH while TBCA and siRNA MAFG worsened these indices. DMF mediated stabilization of Nrf2 reduced expression of intracellular adhesion molecule-1 and increased expression of CK2, and nuclear phosphorylated Nrf2 and MAFG. Conclusion DMF improved neurological outcomes and ameliorated inflammation after experimental ICH in mice. [figure2]