EARLY METABOLIC DYSFUNCTION AGGRAVATES THE MOTOR AND COGNITIVE CONSEQUENCES OF CAROTID ARTERY LIGATION: IMPACT OF ANTITHROMBOTIC DRUG TREATMENT

Abstract

Stroke is a predominant cause of death and disability globally. Extensive evidence support a link between poorly controlled blood glucose, diabetes mellitus, elevated stroke risk, and worsened functional outcomes after stroke. On the other hand, while prediabetes has emerged as a risk factor for several health conditions including cardiovascular dysfunction and cognitive decline, the underlying mechanism is not well understood. Our laboratory recently showed that a metabolically challenged non-obese prediabetic rat model develops perivascular adipose tissue inflammation accompanied by neuroinflammation, neuronal death as well as increased cerebrovascular myogenic tone, which were translated into poor cognitive outcomes. These manifestations were reversed by ameliorating PVAT inflammation. Significantly, adipose tissue inflammation has been linked to vascular remodeling and atherosclerosis through increasing the production of tissue factor, which subsequently triggers the activity of thrombin and factor Xa in vascular smooth muscle and endothelial cells. In the present study, we used carotid artery-ligation to simulate cerebral hypoperfusion and examine the recovery of cerebral circulation in prediabetic rats with and without rivaroxaban treatment. Sham operated and carotid artery ligated prediabetic rats, with or without rivaroxaban treatment underwent a constellation of motor tests in addition to cerebrovascular arteriolar myography. Motor and vascular function were compared to those of control rats. Carotid ligation had worse functional outcomes in the prediabetic rat model with both motor and cognitive decline. Further, factor Xa inhibition by rivaroxaban ameliorated the functional outcomes and enhanced recovery from carotid artery ligation. This was associated with a reversal of the increased cerebrovascular contractility observed in prediabetic rats. Molecular examination were done to assess oxidative stress and neuronal hypoxia in the hippocampus.The worsened motor function observed in prediabetic rats with carotid artery ligation was accompanied by a reduced ability to compensate for cerebrovascular function. This reflected in a state of increased neuroinflammation and brain oxidative stress. Rivaroxaban treatment was able to mitigate the functional and structural damage induced by carotid artery ligation in prediabetic rats.