DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis.

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 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;90:653-669.

• Authors: Chiara Pavan, Anna L R Xavier, Marta Ramos, Jane Fisher, Marios Kritsilis, Adam Linder, Peter Bentzer, Maiken Nedergaard, Iben Lundgaard
• Journal: Annals of neurology (Ann Neurol) Vol. 90 Issue 4 Pg. 653-669 (10 2021) ISSN: 1531-8249 [Electronic] United States
• PMID: 34397111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Chemical References

• Deoxyribonucleases

Topics

• Animals
• Brain (drug effects)
• Cerebrospinal Fluid (drug effects)
• Deoxyribonucleases (pharmacology)
• Extracellular Traps (drug effects)
• Glymphatic System (drug effects)
• Meningitis, Bacterial (drug therapy)
• Meningitis, Pneumococcal (cerebrospinal fluid, drug therapy)
• Rats, Sprague-Dawley
• Rats