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

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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. The goal of the present study was to determine whether the repeated administration of HPβCD 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. Young adult and aged mice were subcutaneously injected with vehicle or HPβCD 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 HPβCD-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, HPβCD reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HPβCD 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 HPβCD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents post-stroke cognitive decline.

Dementia is a common and debilitating sequela of stroke. Currently, there are no available treatments for post-stroke dementia. This 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 HPβCD could be an effective strategy for treating chronic inflammation after stroke and other CNS injuries. We propose that using HPβCD for the prevention of post-stroke dementia could improve recovery and increase long-term quality of life in stroke sufferers.

Danielle A. Becktel, Jacob C. Zbesko, Jennifer B. Frye, Amanda G. Chung, Megan Hayes, Kylie Calderon, Jeffrey W. Grover, Anna Li, Frankie G. Garcia, Marco A. Tavera-Garcia, Rick G. Schnellmann, Hsin-Jung Joyce Wu, Thuy-Vi V. Nguyen and Kristian P. Doyle (2021) BioRxiv.

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