Repeated Administration of 2-Hydroxypropyl-β-Cyclodextrin (HPβCD) Attenuates the Chronic Inflammatory Response to Experimental Stroke
Author
Becktel, D.A.Zbesko, J.C.
Frye, J.B.
Chung, A.G.
Hayes, M.
Calderon, K.
Grover, J.W.
Li, A.
Garcia, F.G.
Tavera-Garcia, M.A.
Schnellmann, R.G.
Wu, H.-J.J.
Nguyen, T.-V.V.
Doyle, K.P.
Affiliation
Department of Immunobiology, University of ArizonaDepartment of Molecular and Cellular Biology, University of Arizona
Arizona Arthritis Center, University of Arizona
Department of Pharmacology and Toxicology, University of Arizona
Department of Neurology, University of Arizona
BIO5 Institute, University of Arizona
Arizona Center on Aging, University of Arizona
Department of Psychology, University of Arizona Department of Neurosurgery, University of Arizona
Issue Date
2022
Metadata
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Society for NeuroscienceCitation
Becktel, D. A., Zbesko, J. C., Frye, J. B., Chung, A. G., Hayes, M., Calderon, K., Grover, J. W., Li, A., Garcia, F. G., Tavera-Garcia, M. A., Schnellmann, R. G., Wu, H.-J. J., Nguyen, T.-V. V., & Doyle, K. P. (2022). Repeated Administration of 2-Hydroxypropyl-β-Cyclodextrin (HPβCD) Attenuates the Chronic Inflammatory Response to Experimental Stroke. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience.Rights
Copyright © 2022 Becktel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that may contribute to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) is an FDA-approved cyclic oligosaccharide that can solubilize and entrap lipophilic substances. 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 mouse model of stroke. To achieve this goal, we subcutaneously injected young adult and aged male mice with vehicle or HPβCD 3 times per week, with treatment beginning 1 week after stroke. We evaluated mice at 7 weeks following stroke using immunostaining, RNA sequencing, lipidomic, 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 preserved NeuN immunoreactivity in the striatum and thalamus and c-Fos immunoreactivity in hippocampal regions. Additionally, HPβCD improved recovery through the protection of hippocampal-dependent spatial working memory and reduction of impulsivity. These results indicate that systemic HPβCD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents poststroke cognitive decline.SIGNIFICANCE STATEMENT Dementia is a common and debilitating sequela of stroke. Currently, there are no available treatments for poststroke 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 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 poststroke dementia could improve recovery and increase long-term quality of life in stroke sufferers. Copyright © 2022 Becktel et al.Note
Open access articleISSN
1529-2401PubMed ID
34819339Version
Final published versionae974a485f413a2113503eed53cd6c53
10.1523/JNEUROSCI.0933-21.2021
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Except where otherwise noted, this item's license is described as Copyright © 2022 Becktel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.