Magnesium therapy improves outcome in Streptococcus pneumoniae meningitis by altering pneumolysin pore formation.
- Hupp S Institute of Anatomy, University of Bern, Bern, Switzerland.
- Ribes S Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
- Seele J Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
- Bischoff C DFG Membrane/Cytoskeleton Interaction Group, Institute of Pharmacology and Toxicology & Rudolf Virchow Center for Experimental Medicine, University of Würzburg, Würzburg, Germany.
- Förtsch C DFG Membrane/Cytoskeleton Interaction Group, Institute of Pharmacology and Toxicology & Rudolf Virchow Center for Experimental Medicine, University of Würzburg, Würzburg, Germany.
- Maier E Rudolf Virchow Center for Experimental Medicine, University of Würzburg, Würzburg, Germany.
- Benz R Rudolf Virchow Center for Experimental Medicine, University of Würzburg, Würzburg, Germany.
- Mitchell TJ Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
- Nau R Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
- Iliev AI Institute of Anatomy, University of Bern, Bern, Switzerland.
- 2017-09-10
Published in:
- British journal of pharmacology. - 2017
Animals
Bacterial Proteins
Brain
Disease Models, Animal
Female
Magnesium Chloride
Meningitis, Pneumococcal
Mice
Mice, Inbred C57BL
Neuroglia
Rats
Rats, Sprague-Dawley
Streptococcus pneumoniae
Streptolysins
Survival Rate
English
BACKGROUND AND PURPOSE
Streptococcus pneumoniae is the most common cause of bacterial meningitis in adults and is characterized by high lethality and substantial cognitive disabilities in survivors. Here, we have studied the capacity of an established therapeutic agent, magnesium, to improve survival in pneumococcal meningitis by modulating the neurological effects of the major pneumococcal pathogenic factor, pneumolysin.
EXPERIMENTAL APPROACH
We used mixed primary glial and acute brain slice cultures, pneumolysin injection in infant rats, a mouse meningitis model and complementary approaches such as Western blot, a black lipid bilayer conductance assay and live imaging of primary glial cells.
KEY RESULTS
Treatment with therapeutic concentrations of magnesium chloride (500 mg·kg-1 in animals and 2 mM in cultures) prevented pneumolysin-induced brain swelling and tissue remodelling both in brain slices and in animal models. In contrast to other divalent ions, which diminish the membrane binding of pneumolysin in non-therapeutic concentrations, magnesium delayed toxin-driven pore formation without affecting its membrane binding or the conductance profile of its pores. Finally, magnesium prolonged the survival and improved clinical condition of mice with pneumococcal meningitis, in the absence of antibiotic treatment.
CONCLUSIONS AND IMPLICATIONS
Magnesium is a well-established and safe therapeutic agent that has demonstrated capacity for attenuating pneumolysin-triggered pathogenic effects on the brain. The improved animal survival and clinical condition in the meningitis model identifies magnesium as a promising candidate for adjunctive treatment of pneumococcal meningitis, together with antibiotic therapy.
Streptococcus pneumoniae is the most common cause of bacterial meningitis in adults and is characterized by high lethality and substantial cognitive disabilities in survivors. Here, we have studied the capacity of an established therapeutic agent, magnesium, to improve survival in pneumococcal meningitis by modulating the neurological effects of the major pneumococcal pathogenic factor, pneumolysin.
EXPERIMENTAL APPROACH
We used mixed primary glial and acute brain slice cultures, pneumolysin injection in infant rats, a mouse meningitis model and complementary approaches such as Western blot, a black lipid bilayer conductance assay and live imaging of primary glial cells.
KEY RESULTS
Treatment with therapeutic concentrations of magnesium chloride (500 mg·kg-1 in animals and 2 mM in cultures) prevented pneumolysin-induced brain swelling and tissue remodelling both in brain slices and in animal models. In contrast to other divalent ions, which diminish the membrane binding of pneumolysin in non-therapeutic concentrations, magnesium delayed toxin-driven pore formation without affecting its membrane binding or the conductance profile of its pores. Finally, magnesium prolonged the survival and improved clinical condition of mice with pneumococcal meningitis, in the absence of antibiotic treatment.
CONCLUSIONS AND IMPLICATIONS
Magnesium is a well-established and safe therapeutic agent that has demonstrated capacity for attenuating pneumolysin-triggered pathogenic effects on the brain. The improved animal survival and clinical condition in the meningitis model identifies magnesium as a promising candidate for adjunctive treatment of pneumococcal meningitis, together with antibiotic therapy.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1111/bph.14027
- PMID 28888095
- Persistent URL
- https://sonar.ch/global/documents/14
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