Repeated Administration of 2-Hydroxypropyl-β-Cyclodextrin (HPβCD) Attenuates the Chronic Inflammatory Response to Experimental Stroke.
2-Hydroxypropyl-beta-cyclodextrin
/ therapeutic use
Age Factors
Animals
Brain
/ drug effects
DNA-Binding Proteins
/ metabolism
Disease Models, Animal
Infarction, Middle Cerebral Artery
/ drug therapy
Inflammation
/ drug therapy
Male
Mice
Nerve Tissue Proteins
/ metabolism
Proto-Oncogene Proteins c-fos
/ metabolism
Treatment Outcome
cholesterol
cyclodextrin
inflammation
lipid
myelin
stroke
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
ISSN: 1529-2401
Titre abrégé: J Neurosci
Pays: United States
ID NLM: 8102140
Informations de publication
Date de publication:
12 01 2022
12 01 2022
Historique:
received:
03
05
2021
revised:
24
08
2021
accepted:
16
11
2021
pubmed:
26
11
2021
medline:
15
2
2022
entrez:
25
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34819339
pii: JNEUROSCI.0933-21.2021
doi: 10.1523/JNEUROSCI.0933-21.2021
pmc: PMC8802936
doi:
Substances chimiques
DNA-Binding Proteins
0
Nerve Tissue Proteins
0
NeuN protein, mouse
0
Proto-Oncogene Proteins c-fos
0
2-Hydroxypropyl-beta-cyclodextrin
1I96OHX6EK
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
325-348Subventions
Organisme : NIA NIH HHS
ID : R01 AG063808
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS096091
Pays : United States
Organisme : RRD VA
ID : I01 RX002079
Pays : United States
Organisme : NIH HHS
ID : S10 OD025016
Pays : United States
Organisme : NINDS NIH HHS
ID : F31 NS105455
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG062781
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG058503
Pays : United States
Informations de copyright
Copyright © 2022 Becktel et al.
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