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

Hupp, Sabrina; Ribes, Sandra; Seele, Jana; Bischoff, Carolin; Förtsch, Christina; Maier, Elke; Benz, Roland; Mitchell, Timothy J; Nau, Roland; Iliev, Asparouh Iliev (2017). Magnesium therapy improves outcome in Streptococcus pneumoniae meningitis by altering pneumolysin pore formation. British journal of pharmacology, 174(23), pp. 4295-4307. Wiley-Blackwell 10.1111/bph.14027

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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.

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