Magnesium therapy improves outcome in Streptococcus pneumoniae meningitis by altering pneumolysin pore formation

Research output: Contribution to journalArticlepeer-review

Authors

  • Sabrina Hupp
  • Sandra Ribes
  • Jana Seele
  • Carolin Bischoff
  • Christina Förtsch
  • Elke Maier
  • Roland Benz
  • Roland Nau
  • Asparouh I Iliev

Colleges, School and Institutes

External organisations

  • DFG Membrane/cytoskeleton Interaction Group, Institute of Pharmacology and Toxicology & Rudolf Virchow Center for Experimental Medicine; University of Würzburg; Versbacherstr. 9 97078 Würzburg Germany
  • Department of Geriatrics; Evangelisches Krankenhaus Göttingen-Weende; An der Lutter 24 37075 Göttingen Germany
  • Rudolf Virchow Center for Experimental Medicine; University of Würzburg; Versbacherstr 9 97078 Würzburg Germany
  • Chair of Microbial Infection and Immunity, Institute of Microbiology and Infection, College of Medical and Dental Sciences; University of Birmingham; Edgbaston Birmingham B15 2TT UK
  • Department of Neuropathology; University Medical Center Göttingen; Robert Koch Str. 40 37075 Göttingen Germany
  • Department of Geriatrics; Evangelisches Krankenhaus Göttingen-Weende; An der Lutter 24 37075 Göttingen Germany
  • Rudolf Virchow Center for Experimental Medicine; University of Würzburg; Versbacherstr 9 97078 Würzburg Germany
  • Institute of Anatomy; University of Bern; Baltzerstrasse 2 3012 Bern Switzerland
  • Chair of Microbial Infection and Immunity, Institute of Microbiology and Infection, College of Medical and Dental Sciences; University of Birmingham; Edgbaston Birmingham B15 2TT UK
  • DFG Membrane/cytoskeleton Interaction Group, Institute of Pharmacology and Toxicology & Rudolf Virchow Center for Experimental Medicine; University of Würzburg; Versbacherstr. 9 97078 Würzburg Germany

Abstract

Background and purpose
Streptococcus pneumoniae is the most common cause of bacterial meningitis in adults and is characterised by high lethality and substantial cognitive disabilities in survivors. Here, we study 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 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 points to magnesium as a promising candidate for adjunctive treatment of pneumococcal meningitis together with antibiotic therapy.

Details

Original languageEnglish
JournalBritish Journal of Pharmacology
Early online date9 Sep 2017
Publication statusE-pub ahead of print - 9 Sep 2017