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DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis

Pavan, Chiara LU ; L. R. Xavier, Anna ; Ramos, Marta LU orcid ; Fisher, Jane LU ; Kritsilis, Marios LU orcid ; Linder, Adam LU ; Bentzer, Peter LU ; Nedergaard, Maiken and Lundgaard, Iben LU (2021) In Annals of Neurology 90(4). p.653-669
Abstract

Objective: Streptococcus pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with high mortality and morbidity worldwide. Diffuse brain swelling is a leading cause of morbidity in S pneumoniae meningitis. We hypothesized that neutrophil extracellular traps (NETs) disrupt cerebrospinal fluid (CSF) transport by the glymphatic system and contribute to edema formation in S pneumoniae meningitis. Methods: We used DNase I treatment to disrupt NETs and then assessed glymphatic function by cisterna magna injections of CSF tracers in a rat model of S pneumoniae meningitis. Results: Our analysis showed that CSF influx into the brain parenchyma, as well as CSF... (More)

Objective: Streptococcus pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with high mortality and morbidity worldwide. Diffuse brain swelling is a leading cause of morbidity in S pneumoniae meningitis. We hypothesized that neutrophil extracellular traps (NETs) disrupt cerebrospinal fluid (CSF) transport by the glymphatic system and contribute to edema formation in S pneumoniae meningitis. Methods: We used DNase I treatment to disrupt NETs and then assessed glymphatic function by cisterna magna injections of CSF tracers in a rat model of S pneumoniae meningitis. Results: Our analysis showed that CSF influx into the brain parenchyma, as well as CSF drainage to the cervical lymph nodes, was significantly reduced in the rat model of S pneumoniae meningitis. Degrading NETs by DNase treatment restored glymphatic transport and eliminated the increase in brain weight in the rats. In contrast, first-line antibiotic treatment had no such effect on restoring fluid dynamics. Interpretation: This study suggests that CSF accumulation is responsible for cerebral edema formation and identifies the glymphatic system and NETs as possible new treatment targets in S pneumoniae meningitis. ANN NEUROL 2021.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Annals of Neurology
volume
90
issue
4
pages
653 - 669
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:34397111
  • scopus:85113271737
ISSN
0364-5134
DOI
10.1002/ana.26186
language
English
LU publication?
yes
id
c76388aa-84b5-4dac-8c9b-c76bf65902bc
date added to LUP
2021-09-06 14:57:14
date last changed
2025-04-08 00:20:42
@article{c76388aa-84b5-4dac-8c9b-c76bf65902bc,
  abstract     = {{<p>Objective: Streptococcus pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with high mortality and morbidity worldwide. Diffuse brain swelling is a leading cause of morbidity in S pneumoniae meningitis. We hypothesized that neutrophil extracellular traps (NETs) disrupt cerebrospinal fluid (CSF) transport by the glymphatic system and contribute to edema formation in S pneumoniae meningitis. Methods: We used DNase I treatment to disrupt NETs and then assessed glymphatic function by cisterna magna injections of CSF tracers in a rat model of S pneumoniae meningitis. Results: Our analysis showed that CSF influx into the brain parenchyma, as well as CSF drainage to the cervical lymph nodes, was significantly reduced in the rat model of S pneumoniae meningitis. Degrading NETs by DNase treatment restored glymphatic transport and eliminated the increase in brain weight in the rats. In contrast, first-line antibiotic treatment had no such effect on restoring fluid dynamics. Interpretation: This study suggests that CSF accumulation is responsible for cerebral edema formation and identifies the glymphatic system and NETs as possible new treatment targets in S pneumoniae meningitis. ANN NEUROL 2021.</p>}},
  author       = {{Pavan, Chiara and L. R. Xavier, Anna and Ramos, Marta and Fisher, Jane and Kritsilis, Marios and Linder, Adam and Bentzer, Peter and Nedergaard, Maiken and Lundgaard, Iben}},
  issn         = {{0364-5134}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{653--669}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Annals of Neurology}},
  title        = {{DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis}},
  url          = {{http://dx.doi.org/10.1002/ana.26186}},
  doi          = {{10.1002/ana.26186}},
  volume       = {{90}},
  year         = {{2021}},
}