Magnesium therapy improves outcome in Streptococcus pneumoniae meningitis by altering pneumolysin pore formation
Open accessAbstract
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: 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.
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Several potential targets and interventions have been tested in animal models and small retrospective human studies.
“Although several potential targets and interventions have been tested in animal models 57 and small retrospective human studies 55”
From Community-acquired acute bacterial meningitis in adults: a clinical update (2019) · cites this paper as [55]
Rifampicin has shown promise as a potential adjunct in human studies.
“has also shown promise as a potential adjunct in human studies.55,56”
From Community-acquired acute bacterial meningitis in adults: a clinical update (2019) · cites this paper as [55]
The Discussion proposes magnesium as an adjunct and recommends a future clinical study; it does not report human studies of rifampicin. Searches for “rifampicin” and “rifampin” found rifampin only in reference titles concerning experimental or infant-rat meningitis, not evidence for the attributed human-study claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredRifampicin has significant anti-inflammatory properties.
“Rifampicin although bacteriostatic has significant anti-inflammatory properties”
From Community-acquired acute bacterial meningitis in adults: a clinical update (2019) · cites this paper as [55]
The Introduction (page unavailable) discusses reduced release of neurotoxic factors with non-bacteriolytic antibiotics, but does not identify rifampicin as having anti-inflammatory properties. Searches for “rifampicin anti-inflammatory,” “rifampin,” and “anti-inflammatory” found rifampin only in reference titles, not a statement supporting the claim. (LLM, conf=0.76)
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Cites
Animal research: Reporting <i>in vivo</i> experiments: The ARRIVE guidelines
Kilkenny, C., Browne, W., Cuthill, I. C., Emerson, M., & Altman, D. G. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00872.x · Cited by 3,625 · see citing works
Animal Research: Reporting <i>in vivo</i> Experiments—The ARRIVE Guidelines
Kilkenny, C., Browne, W., Cuthill, I. C., Emerson, M., & Altman, D. G. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2010.220 · Cited by 2,012 · see citing works
McGrath, J. C., & Lilley, E. (2015) · British Journal of Pharmacology · doi:10.1111/bph.12955 · Cited by 1,321 · see citing works
Southan, C., Sharman, J., Benson, H., Faccenda, E., Pawson, A. J., Alexander, S. P. H., Buneman, O., Davenport, A., McGrath, J., Peters, J., et al. (2015) · Nucleic Acids Res. · doi:10.1093/nar/gkv1037 · Cited by 1,121 · see citing works
Experimental design and analysis and their reporting: new guidance for publication in BJP
Curtis, M. J., Bond, R. A., Spina, D., Ahluwalia, A., Alexander, S. P. H., Giembycz, M. A., Gilchrist, A., Hoyer, D., Insel, P. A., Izzo, A. A., et al. (2015) · British Journal of Pharmacology · doi:10.1111/bph.12856 · Cited by 1,034 · see citing works
Magnesium: Nature's physiologic calcium blocker
Iseri, L. T., & French, J. H. (1984) · American Heart Journal · doi:10.1016/0002-8703(84)90572-6 · Cited by 831 · see citing works
Crowther, C. A. (2003) · JAMA · doi:10.1001/jama.290.20.2669 · Cited by 625 · see citing works
The Concise Guide to PHARMACOLOGY 2015/16: Enzymes
Alexander, S. P. H., Fabbro, D., Kelly, E., Marrion, N. V., Peters, J. A., Benson, H. E., Faccenda, E., Pawson, A. J., Sharman, J. L., Southan, C., et al. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13354 · Cited by 604 · see citing works
Benz, R., Janko, K., Boos, W., & Läuger, P. (1978) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(78)90269-9 · Cited by 507 · see citing works
Self-citationKastenbauer, S., & Pfister, H. (2003) · Brain · doi:10.1093/brain/awg113 · Cited by 481 · see citing works
Animal models in translational medicine: Validation and prediction
Denayer, T., Stöhr, T., & Roy, M. V. (2014) · European Journal of Molecular & Clinical Medicine · doi:10.1016/j.nhtm.2014.08.001 · Cited by 448 · see citing works
Structural Basis of Pore Formation by the Bacterial Toxin Pneumolysin
Tilley, S. J., Orlova, E. V., Gilbert, R. J. C., Andrew, P. W., & Saibil, H. R. (2005) · Cell · doi:10.1016/j.cell.2005.02.033 · Cited by 421 · see citing works
Pathogenesis and pathophysiology of pneumococcal meningitis
Koedel, U., Scheld, W. M., & Pfister, H. (2002) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(02)00450-4 · Cited by 380 · see citing works
Replacement, reduction and refinement.
Flecknell, P. A. (2002) · PubMed · Cited by 380 · see citing works
Bielecki, J., Youngman, P. J., Connelly, P. S., & Portnoy, D. A. (1990) · Nature · doi:10.1038/345175a0 · Cited by 351 · see citing works
A review of progress in understanding the pathophysiology and treatment of brain edema
Marmarou, A. (2007) · Neurosurgical FOCUS · doi:10.3171/foc.2007.22.5.2 · Cited by 333 · see citing works
Magnesium Sulfate for the Treatment of Eclampsia
Euser, A. G., & Cipolla, M. J. (2009) · Stroke · doi:10.1161/strokeaha.108.527788 · Cited by 310 · see citing works
Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades
Blanga‐Kanfi, S., Miranda, H. C., Penn, O., et al. (2009) · BMC Evolutionary Biology · doi:10.1186/1471-2148-9-71 · Cited by 296 · see citing works
Jones, S., & Portnoy, D. A. (1994) · Infection and Immunity · doi:10.1128/iai.62.12.5608-5613.1994 · Cited by 249 · see citing works
The Concise Guide to PHARMACOLOGY 2015/16: Overview
Alexander, S. P. H., Kelly, E., Marrion, N. V., Peters, J. A., Benson, H. E., Faccenda, E., Pawson, A. J., Sharman, J. L., Southan, C., Buneman, O. P., et al. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13347 · Cited by 230 · see citing works
Paton, J. C., Lock, R. A., & Hansman, D. J. (1983) · Infection and Immunity · doi:10.1128/iai.40.2.548-552.1983 · Cited by 207 · see citing works
Canvin, J. R., Marvin, A., Sivakumaran, M., Paton, J. C., Boulnois, G. J., Andrew, P. W., & Mitchell, T. J. (1995) · The Journal of Infectious Diseases · doi:10.1093/infdis/172.1.119 · Cited by 203 · see citing works
Self-citationAwad, M. M., Ellemor, D. M., Boyd, R. L., et al. (2001) · Infection and Immunity · doi:10.1128/iai.69.12.7904-7910.2001 · Cited by 196 · see citing works
Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9)
Iliev, A. I., Stringaris, A. K., Nau, R., & Neumann, H. (2004) · The FASEB Journal · doi:10.1096/fj.03-0670fje · Cited by 192 · see citing works
Self-citationHigh Extracellular Calcium Concentrations Directly Stimulate Osteoclast Apoptosis
Lorget, F., Kamel, S., Mentaverri, R., et al. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2229 · Cited by 161 · see citing works
Medical management of cerebral edema
Raslan, A. M., & Bhardwaj, A. (2007) · Neurosurgical FOCUS · doi:10.3171/foc.2007.22.5.13 · Cited by 137 · see citing works
The Concise Guide to PHARMACOLOGY 2015/16: Ligand‐gated ion channels
Alexander, S. P. H., Peters, J. A., Kelly, E., Marrion, N. V., Benson, H. E., Faccenda, E., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A., et al. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13350 · Cited by 136 · see citing works
Inflammation and brain edema: new insights into the role of chemokines and their receptors
Stamatovic, S. M., Dimitrijevic, O. B., Keep, R. F., & Andjelkovic, A. V. (2006) · Springer eBooks · doi:10.1007/3-211-30714-1_91 · Cited by 125 · see citing works
Stringaris, A. K., Geisenhainer, J., Bergmann, F., Balshüsemann, C., Lee, U., Zysk, G., Mitchell, T. J., Keller, B. U., Kuhnt, U., Gerber, J., et al. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0561 · Cited by 113 · see citing works
Self-citationParenteral magnesium sulfate versus amiodarone in the therapy of atrial tachyarrhythmias
Moran, J. L., Gallagher, J., Peake, S., Cunningham, D. N., Salagaras, M., & Leppard, P. (1995) · Critical Care Medicine · doi:10.1097/00003246-199511000-00005 · Cited by 109 · see citing works
Spreer, A., Kerstan, H., Böttcher, T., Gerber, J., Siemer, A., Zysk, G., Mitchell, T. J., Eiffert, H., & Nau, R. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.8.2649-2654.2003 · Cited by 108 · see citing works
Self-citationA mouse model of Streptococcus pneumoniae meningitis mimicking several features of human disease
Gerber, J., Raivich, G., Wellmer, A., et al. (2001) · Acta Neuropathologica · doi:10.1007/s004010000326 · Cited by 102 · see citing works
Rifampin Reduces Early Mortality in ExperimentalStreptococcus pneumoniaeMeningitis
Nau, R., Wellmer, A., Soto, A., Koch, K., Schneider, O., Schmidt, H., Gerber, J., Michel, U., & Brück, W. (1999) · The Journal of Infectious Diseases · doi:10.1086/314760 · Cited by 99 · see citing works
Self-citationCholesterol-binding cytolytic protein toxins
ALOUF, J. E. (2000) · International Journal of Medical Microbiology · doi:10.1016/s1438-4221(00)80039-9 · Cited by 97 · see citing works
McGinnis, K., Wang, K., & Gnegy, M. E. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0721853.x · Cited by 86 · see citing works
Iliev, A. I., Djannatian, J. R., Nau, R., Mitchell, T. J., & Wouters, F. S. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608213104 · Cited by 85 · see citing works
Self-citationBenz, R., Ishii, J., & Nakae, T. (1980) · The Journal of Membrane Biology · doi:10.1007/bf01869348 · Cited by 84 · see citing works
Self-citationMagnesium as a neuroprotectant in cardiac surgery: A randomized clinical trial
Bhudia, S. K., Cosgrove, D. M., Naugle, R. I., Rajeswaran, J., Lam, B.-K., Walton, E., Petrich, J., Palumbo, R. C., Gillinov, A. M., Apperson-Hansen, C., et al. (2006) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2005.11.018 · Cited by 80 · see citing works
Mathew, J. P., White, W. D., Schinderle, D. B., et al. (2013) · Stroke · doi:10.1161/strokeaha.113.002703 · Cited by 79 · see citing works
Wellmer, A., Zysk, G., Gerber, J., Kunst, T., von Mering, M., Bunkowski, S., Eiffert, H., & Nau, R. (2002) · Infection and Immunity · doi:10.1128/iai.70.11.6504-6508.2002 · Cited by 78 · see citing works
Self-citationMechanisms involved in the antiplatelet activity of magnesium in human platelets
Sheu, J., Hsiao, G., Shen, M., et al. (2002) · British Journal of Haematology · doi:10.1046/j.1365-2141.2002.03967.x · Cited by 74 · see citing works
Salha, D., Szeto, J., Myers, L. E., et al. (2012) · Infection and Immunity · doi:10.1128/iai.06348-11 · Cited by 65 · see citing works
Paula Sperry, S., Jorge Carvajal, C., & P-G, C. V. (2011) · Revista chilena de obstetricia y ginecología · doi:10.4067/s0717-75262011000200012 · Cited by 61 · see citing works
Bacterial Pore-Forming Cytolysins Induce Neuronal Damage in a Rat Model of Neonatal Meningitis
Reiß, A., Braun, J., Jäger, K., Freyer, D., Laube, G., Bührer, C., Felderhoff‐Müser, U., Stadelmann, C., Nizet, V., & Weber, J. R. (2010) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiq047 · Cited by 53 · see citing works
Wippel, C., Maurer, J., Förtsch, C., Hupp, S., Bohl, A., Ma, J., Mitchell, T. J., Bunkowski, S., Brück, W., Nau, R., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003380 · Cited by 52 · see citing works
Self-citationMeningitis in Neonates: Bench to Bedside
Grandgirard, D., & Leib, S. L. (2010) · Clinics in Perinatology · doi:10.1016/j.clp.2010.05.004 · Cited by 46 · see citing works
Liechti, F. D., Grandgirard, D., & Leib, S. L. (2015) · Future Microbiology · doi:10.2217/fmb.15.43 · Cited by 44 · see citing works
Permeability of human brain tumor to 99mTc-glucoheptonate and 99mTc-albumin
Neuwelt, E. A., Specht, H. D., & Hill, S. A. (1986) · Journal of neurosurgery · doi:10.3171/jns.1986.65.2.0194 · Cited by 43 · see citing works
Wall, E. C., Gordon, S. B., Hussain, S., et al. (2012) · Clinical Infectious Diseases · doi:10.1093/cid/cir926 · Cited by 43 · see citing works
The role of magnesium in traumatic brain injury.
van den Heuvel, C., & Vink, R. (2004) · PubMed · Cited by 43 · see citing works
Mack, W. J., Kellner, C. P., Sahlein, D. H., et al. (2009) · Journal of neurosurgery · doi:10.3171/2008.9.17671 · Cited by 40 · see citing works
Grandgirard, D., Burri, M., Agyeman, P., & Leib, S. L. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00674-12 · Cited by 38 · see citing works
Iliev, A. I., Djannatian, J. R., Opazo, F., Gerber, J., Nau, R., Mitchell, T. J., & Wouters, F. S. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06538.x · Cited by 35 · see citing works
Self-citationMagnesium Sulfate for Acute Traumatic Brain Injury
Li, W., Bai, Y.-A., Li, Y., Liu, K., Wang, M., Xu, G.-Z., Shang, H.-L., & Li, Y.-F. (2015) · Journal of Craniofacial Surgery · doi:10.1097/scs.0000000000001339 · Cited by 34 · see citing works
Douce, G. R., Ross, K., Cowan, G. J. M., et al. (2010) · Vaccine · doi:10.1016/j.vaccine.2010.02.014 · Cited by 34 · see citing works
Metal ions affect neuronal membrane fluidity of rat cerebral cortex
Ohba, S., Hiramatsu, M., Edamatsu, R., et al. (1994) · Neurochemical Research · doi:10.1007/bf00971570 · Cited by 33 · see citing works
Hupp, S., Heimeroth, V., Wippel, C., et al. (2011) · Glia · doi:10.1002/glia.21256 · Cited by 32 · see citing works
Self-citationNeuhaus, R., & Cachelin, A. B. (1990) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1990.0069 · Cited by 30 · see citing works
Amagasa, M., Ogawa, A., & Yoshimoto, T. (1990) · Brain Research · doi:10.1016/0006-8993(90)90242-4 · Cited by 30 · see citing works
Magnesium chloride or magnesium sulfate: a genuine question.
Durlach, J., Guiet-Bara, A., Pagès, N., Bac, P., & Bara, M. (2005) · PubMed · Cited by 30 · see citing works
Measurement of edema in the nervous system
Tengvar, C., Forss�n, M., Hultstr�m, D., et al. (1982) · Acta Neuropathologica · doi:10.1007/bf00685382 · Cited by 29 · see citing works
Sun, L., Kosugi, Y., Kawakami, E., et al. (2009) · Magnesium Research · doi:10.1684/mrh.2009.0186 · Cited by 28 · see citing works
The mechanism of pneumolysin‐induced cochlear hair cell death in the rat
Beurg, M., Hafidi, A., Skinner, L. J., et al. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2005.092478 · Cited by 27 · see citing works
IgG Penetration into the Cerebrospinal Fluid in a Rabbit Model of Meningitis
Gigliotti, F., Lee, D., Insel, R. A., et al. (1987) · The Journal of Infectious Diseases · doi:10.1093/infdis/156.2.394 · Cited by 27 · see citing works
Experimental studies of pneumococcal meningitis.
Brandt, C. (2010) · PubMed · Cited by 26 · see citing works
Deletion of a Cation Transporter Promotes Lysis in Streptococcus pneumoniae
Neef, J., Andisi, V. F., Kim, K. S., Kuipers, O. P., & Bijlsma, J. J. E. (2011) · Infection and Immunity · doi:10.1128/iai.00677-10 · Cited by 25 · see citing works
Wippel, C., Förtsch, C., Hupp, S., Maier, E., Benz, R., Ma, J., Mitchell, T. J., & Iliev, A. I. (2011) · The Journal of Infectious Diseases · doi:10.1093/infdis/jir434 · Cited by 25 · see citing works
Self-citationZinc Protection against Pneumolysin Toxicity on Rat Cochlear Hair Cells
Franco‐Vidal, V., Beurg, M., Darrouzet, V., et al. (2007) · Audiology and Neurotology · doi:10.1159/000108763 · Cited by 18 · see citing works
Nagahama, M., Otsuka, A., Oda, M., et al. (2007) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2007.08.016 · Cited by 17 · see citing works
How I do it: sample size calculations
O’Hara, J. (2008) · Clinical Otolaryngology · doi:10.1111/j.1749-4486.2008.01668.x · Cited by 12 · see citing works
Ravens, U., Guo-shu, L., Vandeplassche, G., et al. (1992) · Cardiovascular Drugs and Therapy · doi:10.1007/bf00050917 · Cited by 4 · see citing works
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Community-acquired acute bacterial meningitis in adults: a clinical update
Ellis, J., Luintel, A., Chandna, A., & Heyderman, R. S. (2019) · British Medical Bulletin · doi:10.1093/bmb/ldz023 · Cited by 12 · see citing works
- Authors
- Hupp, S., Ribes, S., Seele, J., Bischoff, C., Förtsch, C., Maier, E., Benz, R., Mitchell, T. J., Nau, R., & Iliev, A. I.
- Affiliations
- University of Bern (CH)
- Universitätsmedizin Göttingen (DE)
- University of Würzburg (DE)
- University of Birmingham (GB)
- Corresponding author
- Iliev, Asparouh I
- ORCID
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2017-10-19
- Volume
- 174
- Issue
- 23
- Pages
- 4295-4307
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC5715590
- OpenAlex
- W2750741543
- Cited by
- 12
- References
- 71
- Citations by year
- 2023: 4 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 1
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_160136/1)
- Universität Bern
- Deutsche Forschungsgemeinschaft
- Julius-Maximilians-Universität Würzburg
- Wellcome Trust (WT094762MA)
- European Science Foundation
- Topics
- Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
- Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Streptococcal Infections and Treatments
- Keywords
- magnesium supplementation, Streptococcus pneumoniae, pneumococcal meningitis, pneumolysin, pore formation, divalent ions, cerebral edema, glial cells, neuroprotection, adjunctive therapy
- MeSH terms
- Animals, Bacterial Proteins, Brain, Disease Models, Animal, Female, Meningitis, Pneumococcal, Mice, Inbred C57BL, Neuroglia, Streptococcus pneumoniae, Streptolysins, Magnesium Chloride, Survival Rate, Rats, Sprague-Dawley, Mice, Rats
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