NLRP3 Inflammasome-Mediated Uncoupling of Hippocampal Vasoneuronal Communications in Diabetes: Relevance to Cognitive Impairment and Stroke

Abstract

Diabetes is a prevalent chronic disease that affects over 29 million individuals in the United States and 422 million people worldwide as of 2017. Given the high mortality and morbidity associated with diabetes due to its complications including retinopathy, chronic kidney disease, peripheral neuropathy, heart disease and stroke, this increase in incidence of diabetes creates many clinical, social and economic problems. A silent, but unrecognized complication of diabetes is cognitive impairment, which ranges from mild cognitive impairment to dementia. The increased risk and incidence of stroke amplifies these cognitive deficits. The objectives of this dissertation were to 1) determine the role and mechanism(s) by which diabetes worsens cognitive decline and 2) determine the extent and mechanism by which NLRP3 activation contributes to poor cognitive function after stroke in diabetes. To investigate these objectives, feeding rats a high fat diet and administering a low dose of streptozotocin was used as a clinically relevant diet-enhanced model of diabetes. Stroke was induced through either transient MCAO (60 or 90 min) or embolic MCAO. Embolic stroke caused more severe hippocampal neurovascular injury, microglial activation and cognitive decline in diabetes as compared to stroke induced by a shorter 60 min suture occlusion of the MCA. Diabetic females were more sensitive to ischemic injury than males. Furthermore, hippocampal vascularization patterns at baseline and after ischemic injury differed in males and females and despite these sex differences in the extent and patterns of hippocampal neurovascular injury, diabetes worsened cognitive outcomes in both sexes. Collectively, these first studies provide a preclinical foundation for future studies addressing cognitive impairment in diabetes in both sexes. NLRP3 inflammasome, which cleaves IL-1β and IL-18 into their active forms, was upregulated in diabetes and amplified following ischemia. Inhibition of the NLRP3 inflammasome with MCC950, a specific small molecule inhibitor of NLRP3 activation, improved post-stroke cognition, reduced hippocampal cell death, was associated with less leaky vasculature, and blunted chronic inflammation in the hippocampus after 90-min MCAO. MCC950 did not seem to provide neuroprotection to the neuron through the mBDNF, but did reduce cell death after hypoxia/reoxygenation in vitro. These results are the first to provide essential data showing that MCC950 has the potential to become a therapeutic agent to prevent neurovascular remodeling and worsened cognitive decline in diabetic patients following stroke. Collectively, this work may provide a piece of the puzzle explaining how diabetes leads to cognitive impairment and worsens outcome following acute ischemic injury, and it provides a potential therapeutic target to treat cognitive impairment after stroke, especially in diabetic patients.