Comprehensive assessment of blood-brain barrier opening and sterile inflammatory response: unraveling the therapeutic window.
Blood–brain barrier opening
Focused ultrasound
Magnetic resonance imaging
Microbubbles
Sterile inflammatory response
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
24 Jul 2024
24 Jul 2024
Historique:
received:
04
04
2024
accepted:
17
07
2024
medline:
24
7
2024
pubmed:
24
7
2024
entrez:
23
7
2024
Statut:
epublish
Résumé
Microbubbles (MBs) combined with focused ultrasound (FUS) has emerged as a promising noninvasive technique to permeabilize the blood-brain barrier (BBB) for drug delivery into the brain. However, the safety and biological consequences of BBB opening (BBBO) remain incompletely understood. This study aims to investigate the effects of two parameters mediating BBBO: microbubble volume dose (MVD) and mechanical index (MI). High-resolution MRI-guided FUS was employed in mouse brains to assess BBBO by manipulating these two parameters. Afterward, the sterile inflammatory response (SIR) was studied 6 h post-FUS treatment. Results demonstrated that both MVD and MI significantly influenced the extent of BBBO, with higher MVD and MI leading to increased permeability. Moreover, RNA sequencing revealed upregulation of major inflammatory pathways and immune cell infiltration after BBBO, indicating the presence and extent of SIR. Gene set enrichment analysis identified 12 gene sets associated with inflammatory responses that were significantly upregulated at higher MVD or MI. A therapeutic window was established between therapeutically relevant BBBO and the onset of SIR, providing operating regimes to avoid damage from stimulation of the NFκB pathway via TNFɑ signaling to apoptosis. These results contribute to the optimization and standardization of BBB opening parameters for safe and effective drug delivery to the brain and further elucidate the underlying molecular mechanisms driving sterile inflammation.
Identifiants
pubmed: 39043894
doi: 10.1038/s41598-024-67916-8
pii: 10.1038/s41598-024-67916-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
17036Subventions
Organisme : NIH HHS
ID : R01 CA239465
Pays : United States
Informations de copyright
© 2024. The Author(s).
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