Sevda Lule1, Limin Wu1, Lauren M McAllister1, William J Edmiston1, Joon Yong Chung1, Emily Levy1, Yi Zheng1, Peter J Gough1, John Bertin1, Alexei Degterev1, Eng H Lo1, Michael J Whalen2. 1. From the Neuroscience Center and Department of Pediatrics (S.L., L.W., L.M.M., W.J.E., J.Y.C., E.L., M.J.W.), Radiology (Y.Z., E.H.L.), and Department of Neurology (E.H.L.), Massachusetts General Hospital and Harvard Medical School, Charlestown; Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA (P.J.G., J.B.); and Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.D.). 2. From the Neuroscience Center and Department of Pediatrics (S.L., L.W., L.M.M., W.J.E., J.Y.C., E.L., M.J.W.), Radiology (Y.Z., E.H.L.), and Department of Neurology (E.H.L.), Massachusetts General Hospital and Harvard Medical School, Charlestown; Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA (P.J.G., J.B.); and Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.D.). MWhalen@harvard.mgh.edu.
Abstract
BACKGROUND AND PURPOSE: Recent studies using cultured cells and rodent intracerebral hemorrhage (ICH) models have implicated RIPK1 (receptor interacting protein kinase-1) as a driver of programmed necrosis and secondary injury based on use of chemical inhibitors. However, these inhibitors have off-target effects and cannot be used alone to prove a role for RIPK1. The aim of the current study was to examine the effect of genetic inhibition of the kinase domain of RIPK1 in a mouse ICH model. METHODS: We subjected 2 lines of mice with RIPK1 point mutations of the kinase domain (K45A and D138N), rendering them kinase inactive, to autologous blood ICH and measured acute cell death and functional outcome. RESULTS: Compared with wild-type controls, RIPK1K45A/K45A and RIPK1D138N/D138N had significantly less cells with plasmalemma permeability, less acute neuronal cell death, less weight loss and more rapid weight gain to baseline, and improved performance in a Morris water maze paradigm after autologous blood ICH. In addition, mice systemically administered GSK'963, a potent, specific, brain penetrant small molecule RIPK1 inhibitor, had reduced acute neuronal death at 24 hours after ICH. CONCLUSIONS: The data show that the kinase domain of RIPK1 is a disease driver of ICH, mediating both acute cell death and functional outcome, and support development of RIPK1 inhibitors as therapeutic agents for human ICH.
BACKGROUND AND PURPOSE: Recent studies using cultured cells and rodent intracerebral hemorrhage (ICH) models have implicated RIPK1 (receptor interacting protein kinase-1) as a driver of programmed necrosis and secondary injury based on use of chemical inhibitors. However, these inhibitors have off-target effects and cannot be used alone to prove a role for RIPK1. The aim of the current study was to examine the effect of genetic inhibition of the kinase domain of RIPK1 in a mouseICH model. METHODS: We subjected 2 lines of mice with RIPK1 point mutations of the kinase domain (K45A and D138N), rendering them kinase inactive, to autologous blood ICH and measured acute cell death and functional outcome. RESULTS: Compared with wild-type controls, RIPK1K45A/K45A and RIPK1D138N/D138N had significantly less cells with plasmalemma permeability, less acute neuronal cell death, less weight loss and more rapid weight gain to baseline, and improved performance in a Morris water maze paradigm after autologous blood ICH. In addition, mice systemically administered GSK'963, a potent, specific, brain penetrant small molecule RIPK1 inhibitor, had reduced acute neuronal death at 24 hours after ICH. CONCLUSIONS: The data show that the kinase domain of RIPK1 is a disease driver of ICH, mediating both acute cell death and functional outcome, and support development of RIPK1 inhibitors as therapeutic agents for humanICH.
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