Repurposing NEXLETOL for the treatment of ischemic stroke

Tulane University Of Louisiana, New Orleans LA

Investigators

Linked publications & trials

Abstract

Ischemic stroke is the third leading cause of death and long-term disability worldwide, with approximately 800,000 cases annually in the U.S. Dyslipidemia, a major cardiometabolic disorder, significantly increases stroke risk and affects 35–50% of patients. It is associated with worse outcomes in stroke patients and exacerbates brain injury in animal models by impairing neurovascular function, including blood-brain barrier (BBB) disruption and neuroinflammation. Bioenergetic dysfunction has emerged as a key mechanism underlying these effects. Dyslipidemia disrupts glucose metabolism and mitochondrial function, amplifying inflammation and stroke-related damage. Enhancing fatty acid oxidation (FAO) can restore bioenergetic balance, benefiting endothelial cells and microglia. In our pilot study, we observed impaired FAO and tricarboxylic acid (TCA) cycle activity in the cerebral microvasculature and microglia during acute stroke. NEXLETOL® (ETC-1002, bempedoic acid), an ACLY inhibitor and AMPK activator recently FDA-approved for hypercholesterolemia, offers a promising strategy to target neurovascular bioenergetic dysfunction in dyslipidemic stroke. Our preliminary data show that ETC-1002 enhances FAO and mitochondrial function, reduces BBB disruption, mitigates microglial activation, and improves neurological outcomes in a mouse stroke model. We hypothesize that dyslipidemia worsens acute bioenergetic dysfunction in cerebral microvascular endothelial cells and microglia, leading to increased BBB leakage and neuroinflammation following stroke. ETC-1002 restores FAO, alleviating neurovascular dysfunction and improving neurological outcomes. This will be tested using high-fat diet (HFD)-induced dyslipidemic and control mice subjected to experimental stroke, with ETC-1002 administered post-stroke. In Aim 1, we will investigate the role of ETC- 1002 in mitigating cerebral microvascular metabolic/bioenergetics dysregulation and acute BBB disruption after ischemic stroke with dyslipidemia. In Aim 2, we will the role of ETC-1002 administration in microglia metabolic/bioenergetics dysregulation and acute neuroinflammation after ischemic stroke with dyslipidemia. In Aim 3, we will evaluate the therapeutic potential of ETC-1002 in mitigating acute brain damage and improving long-term neurological outcomes in adult and aged stroke mice with/without dyslipidemia. This study aims to preclinically evaluate ETC-1002 as a novel therapy for stroke with dyslipidemia while providing critical insights into the role of neurovascular bioenergetic dysfunction in stroke pathology.