Abstract 12073: Compound K811 Prevents Vascular Cognitive Impairment by Inhibiting Apoptosis Signal-Regulating Kinase 1
Background: There are currently no specific strategies for the treatment or prevention of vascular dementia (VaD). We sought to demonstrate that apoptosis signal-regulating kinase 1 (ASK1) is a key molecule in VaD induced by chronic cerebral ischemia in the white matter (WM).
Methods:  Chronic cerebral ischemia in WM, including the corpus callosum, was induced in C57BL/6J (Wild type) and ASK1 deficient mice (ASK1-/-) via bilateral common carotid artery stenosis (BCAS) surgery. Wild type and ASK1-/- mice were subdivided into sham and BCAS groups. We evaluated cognitive function on the Y-maze test, WM lesions and glial cell activation in the corpus callosum. Extravasated Evans blue in the corpus callosum at 3 days post BCAS was measured to evaluate blood brain barrier (BBB) breakdown.  Mouse cerebral endothelial cells were isolated to evaluate the effect of tumor necrosis-α (TNFα) stimulation on the tight junctions.  Wild type mice subjected to BCAS were treated with either vehicle or compound K811, a specific ASK1 inhibitor.
Results:  BCAS caused cognitive decline due to WM lesions and glial cell activation in Wild type but not in ASK1-/- mice. Phosphorylated-ASK1 in Wild type brains increased persistently after BCAS. Phosphorylated-p38 and TNFα expression increased in cerebral endothelial cells at the corpus callosum of Wild type after BCAS, but not in ASK1-/- mice. BCAS decreased claudin-5 expression and disrupted the BBB in the corpus callosum of Wild type, but not in ASK1-/- mice. Cerebral nitrotyrosine after BCAS increased in both mice. Cerebral phosphorylated-ASK1 did not increase in Wild type mice treated with NADPH-oxidase inhibitor. A p38-inhibitor and NADPH-oxidase inhibitor mimicked the protective effects of ASK1-deficiency against VaD.  In vitro, TNFα stimulation caused the disruption of endothelial tight junctions in Wild type, but not in ASK1-/- mice.  K811, though not reducing blood pressure, prevented cognitive decline, WM lesions and glial cell activation in the Wild type BCAS mice.
Conclusions: An oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through BBB-breakdown via the disruption of endothelial tight junctions. K811 is a promising therapeutic agent for preventing VaD.
- © 2013 by American Heart Association, Inc.