Enhanced Mitochondrial Function Increases Effectiveness of Post-Stroke Rehabilitation

This project will investigate the efficacy of 2-hydroxypropyl-β-cyclodextrin (HPCD) in reducing stroke-induced tissue loss and enhancing motor rehabilitative training after stroke. The proposed mechanism of action is the removal of proinflammatory myelin lipid debris and the restoration of mitochondrial function in myeloid cells after stroke. This is supported by our recent published studies that reveal that the processing and clearance of cholesterol and other lipid debris derived from myelin drives a chronic inflammatory response in the focal ischemic lesion of the sensorimotor cortex (SMC) in an experimental model of stroke. HPCD entraps and solubilizes lipid debris, upregulates genes involved in lipid metabolism, and downregulates genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, HPβCD reduces the accumulation of lipid droplets and mitochondrial stress within myeloid cells in stroke infarcts. Repeated administration of HPβCD also preserves neuronal immunoreactivity in the striatum, thalamus, and hippocampus. Additional data reveals that HPβCD improves recovery through the protection of hippocampal-dependent spatial working memory and by reducing impulsivity. These results indicate that systemic HPβCD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration. Therefore, we hypothesize that treating mice with HPβCD after stroke and during rehabilitative training will improve motor outcomes in a mouse model of sensorimotor stroke. To test this hypothesis, we will first optimize the dose using mitochondrial function within myeloid cells, markers of inflammation and neurodegeneration, and cell type specific spatial transcriptomics as functional readouts (Aim 1). We will then investigate the mechanism by which HPβCD alleviates lipid build-up and mitochondrial dysfunction within myeloid cells (Aim 2). We will then determine the extent to which our optimized dose enhances rehabilitative training induced behavioral improvements and brain remodeling (Aim 3). Successful completion of these studies will reveal the dose, mechanism, and ability of HPβCD to support rehabilitative training during recovery from stroke. Since HPβCD is an FDA approved compound, successful completion of these studies in accordance with Stroke Therapy Academic Industry Roundtable (STAIR) guidelines could rapidly lead to clinical trials for human stroke survivors.