Repeated administration of 2-hydroxypropyl-β-cyclodextrin (HPβCD) attenuates the chronic inflammatory response to experimental stroke

Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that contributes to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-hydroxypropyl-{beta}-cyclodextrin (HP{beta}CD) is an FDA-approved cyclic oligosaccharide developed to solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HP{beta}CD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion + hypoxia (DH) mouse model of stroke. We subcutaneously injected young adult and aged mice with vehicle or HP{beta}CD three times per week for up to 7 weeks following stroke and evaluated them using immunostaining, RNA sequencing, lipidomics, and behavioral analyses. Chronic stroke infarct and peri-infarct regions of HP{beta}CD-treated mice were characterized by an upregulation of genes involved in lipid metabolism and a downregulation of genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, HP{beta}CD reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HP{beta}CD also improved recovery through the preservation of neurons in the striatum and thalamus, induction of c-Fos in hippocampal regions, protection of hippocampal-dependent spatial working memory, and reduction in impulsivity at 7 weeks after stroke. These results indicate that systemic HP{beta}CD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents post-stroke cognitive decline. Significance StatementDementia is a common and debilitating sequela of stroke. Currently, there are no available treatments for post-stroke dementia. Our study shows that lipid metabolism is disrupted in chronic stroke infarcts, which causes an accumulation of uncleared lipid debris and correlates with a chronic inflammatory response. To our knowledge, these substantial changes in lipid homeostasis have not been previously recognized or investigated in the context of ischemic stroke. We also provide a proof of principle that solubilizing and entrapping lipophilic substances using HP{beta}CD could be an effective strategy for treating chronic inflammation after stroke and other CNS injuries. We propose that using HP{beta}CD for the prevention of post-stroke dementia could improve recovery and increase long-term quality of life in stroke sufferers.