Abstract 106: NLRP3 Inflammasome Inhibition With MCC950 Improves Diabetes-Mediated Cognitive Impairment and Vasoneuronal Remodeling After Ischemia

Abstract

Diabetes increases the risk and worsens the progression of cognitive impairment via the greater occurrence of small vessel disease and stroke. While NLRP3 inflammasome signaling has been implicated in the development of neurodegenerative diseases, little is known about the impact of NLRP3 activation on functional and structural interaction within the neurovascular unit (NVU) in diabetes. Endothelial cells are at the center of NVU and produce trophic factors such as BDNF contributing to neuronal survival, known as vasotrophic coupling. Therefore, the goals of this study were to determine the role of NLRP3 activation: 1) on hippocampal NVU remodeling and cognitive outcome after stroke in diabetes, and 2) on vasotrophic uncoupling between endothelial cells and hippocampal neurons after hypoxic injury in diabetes-mimicking conditions. Control and high-fat diet/STZ induced diabetic male rats were treated with saline or MCC950 (3mg/kg), a small molecule inhibitor of NLRP3, after reperfusion following a 90-min MCAO. Cognition was assessed. Neuronal death, blood-brain barrier (BBB) permeability and glial remodeling was measured on Day 14 after stroke. BDNF was measured in endothelial and hippocampal cell cultures under hypoxic and diabetes-mimicking condition with and without NLRP3 inhibition. Diabetes increased neuronal degeneration, BBB permeability, disrupted AQP4 polarity, impaired cognitive function and increased NLRP3 activation after ischemia. Inhibition with MCC950 improved cognitive function and NVU indices after stroke in diabetic animals and prevented hypoxia-mediated decrease in BDNF secretion. These results are the first to provide essential data showing MCC950 has the potential to become a therapeutic to prevent neurovascular remodeling and worsened cognitive decline in diabetic patients following stroke.