Inhibition of matrix metalloproteinases attenuates brain damage in experimental meningococcal meningitis

Ricci, Susanna; Grandgirard, Denis; Wenzel, Michael; Braccini, T; Salvatore, Paola; Oggioni, Marco R.; Leib, Stephen L.; Koedel, Uwe

doi:10.1186/s12879-014-0726-6

Cited by 30 publications

(36 citation statements)

References 48 publications

(64 reference statements)

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“…High concentrations of MMP-9 are associated with neurological sequelae after meningitis [187]. The broad-spectrum MMP inhibitor batimastat administered 1 h before and 24 h after infection reduced the blood-brain barrier breakdown and intracerebral hemorrhage, and tended to reduce hippocampal injury and increase survival in murine experimental meningococcal meningitis [188]. Several classes of MMP inhibitors including the second-generation MMP inhibitor RS-130830, which proved to be safe in clinical trials for osteoarthritis and hepatitis C, were able to reduce neocortical but not hippocampal injury when given 3 h after the induction of Str.…”

Section: Inhibitors Of Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

Bacterial meningitis: an update of new treatment options

Nau

Djukic

Spreer

et al. 2015

Expert Review of Anti-infective Therapy

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The outcome of bacterial meningitis critically depends on the rapid initiation of bactericidal antibiotic therapy and adequate management of septic shock. In community-acquired meningitis, the choice of an optimum initial empirical antibiotic regimen depends on the regional resistance patterns. Pathogens resistant to antibacterials prevail in nosocomial bacterial meningitis. Dexamethasone is recommended as adjunctive therapy for community-acquired meningitis in developed countries. In comatose patients, aggressive measures to lower intracranial pressure <20 mmHg (in particular, external ventriculostomy, osmotherapy and temporary hyperventilation) were effective in a case-control study. Although many experimental approaches were protective in animal models, none of them has been proven effective in patients. Antibiotics, which are bactericidal but do not lyse bacteria, and inhibitors of matrix metalloproteinases or complement factor C5 appear the most promising therapeutic options. At present, vaccination is the most efficient method to reduce disease burden. Palmitoylethanolamide appears promising to enhance the resistance of the brain to infections.

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Section: Inhibitors Of Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

Bacterial meningitis: an update of new treatment options

Nau

Djukic

Spreer

et al. 2015

Expert Review of Anti-infective Therapy

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“…Matrix metalloproteinases and ADAMs function as ECM degrading enzymes and sheddases, thereby controlling BBB breakdown and production of inflammatory cytokines [15]. In experimental bacterial meningitis, MMP and ADAM inhibitors significantly reduce CSF levels of MMPs and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10) [128,132,[167][168][169]. Notably, CSF levels of TNF-α are also significantly reduced by MMP inhibitors (MMPIs) without specificity for ADAM17 (i.e., Trocade) [167], indicating that MMPIs are able to indirectly reduce pro-inflammatory cytokine production apart from direct ADAM17 inhibition.…”

Section: Neuroinflammation and Bbb Breakdownmentioning

confidence: 99%

“…Since metalloproteinases are central regulators of BBB breakdown during bacterial meningitis (discussed above), their inhibition during the acute disease is a valuable therapeutic strategy to reduce cortical necrosis. Pre-treatment or treatment early in the course of disease with MMPIs is associated with reduced cortical necrosis in pneumococcal meningitis [128,132,167,168,172,173] and with lower rates of intracerebral hemorrhage in meningococcal meningitis [169]. This neuroprotective effect is, however, reduced when the application of the inhibitors is delayed until the time of antibiotic therapy at the first appearance of disease symptoms [127,174].…”

Section: Cortical Necrosismentioning

confidence: 99%

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Muri

Leppert

Grandgirard

et al. 2019

Cell. Mol. Life Sci.

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Metalloproteinases-such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs)-are involved in various diseases of the nervous system but also contribute to nervous system development, synaptic plasticity and neuroregeneration upon injury. MMPs and ADAMs proteolytically cleave many substrates including extracellular matrix components but also signaling molecules and receptors. During neuroinfectious disease with associated neuroinflammation, MMPs and ADAMs regulate blood-brain barrier breakdown, bacterial invasion, neutrophil infiltration and cytokine signaling. Specific and broad-spectrum inhibitors for MMPs and ADAMs have experimentally been shown to decrease neuroinflammation and brain damage in diseases with excessive neuroinflammation as a common denominator, such as pneumococcal meningitis and multiple sclerosis, thereby improving the disease outcome. Timing of metalloproteinase inhibition appears to be critical to effectively target the cascade of pathophysiological processes leading to brain damage without inhibiting the neuroregenerative effects of metalloproteinases. As the critical role of metalloproteinases in neuronal repair mechanisms and regeneration was only lately recognized, the original idea of chronic MMP inhibition needs to be conceptually revised. Recently accumulated research urges for a second chance of metalloproteinase inhibitors, which-when correctly applied and dosed-harbor the potential to improve the outcome of different neuroinflammatory diseases.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…Mice were infected by the i.cist. route as previously described (27,30,70). Bacteria for mouse challenge were prepared as previously reported (27), thawed, centrifuged for 15 min at 1,500 ϫ g, and suspended in GC broth with iron dextran (5 mg/kg; Sigma-Aldrich/Merck KGaA).…”

Section: Methodsmentioning

confidence: 99%

Virulence Traits of a Serogroup C Meningococcus and Isogenic cssA Mutant, Defective in Surface-Exposed Sialic Acid, in a Murine Model of Meningitis

et al. 2019

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In serogroup C Neisseria meningitidis, the cssA (siaA) gene codes for an UDP-N-acetylglucosamine 2-epimerase that catalyzes the conversion of UDP-N-acetyl-α-d-glucosamine into N-acetyl-d-mannosamine and UDP in the first step in sialic acid biosynthesis. This enzyme is required for the biosynthesis of the (α2→9)-linked polysialic acid capsule and for lipooligosaccharide (LOS) sialylation. In this study, we have used a reference serogroup C meningococcal strain and an isogenic cssA knockout mutant to investigate the pathogenetic role of surface-exposed sialic acids in a model of meningitis based on intracisternal inoculation of BALB/c mice. Results confirmed the key role of surface-exposed sialic acids in meningococcal pathogenesis. The 50% lethal dose (LD50) of the wild-type strain 93/4286 was about four orders of magnitude lower than that of the cssA mutant. Compared to the wild-type strain, the ability of this mutant to replicate in brain and spread systemically was severely impaired. Evaluation of brain damage evidenced a significant reduction in cerebral hemorrhages in mice infected with the mutant in comparison with the levels in those challenged with the wild-type strain. Histological analysis showed the typical features of bacterial meningitis, including inflammatory cells in the subarachnoid, perivascular, and ventricular spaces especially in animals infected with the wild type. Noticeably, 80% of mice infected with the wild-type strain presented with massive bacterial localization and accompanying inflammatory infiltrate in the corpus callosum, indicating high tropism of meningococci exposing sialic acids toward this brain structure and a specific involvement of the corpus callosum in the mouse model of meningococcal meningitis.

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Inhibition of matrix metalloproteinases attenuates brain damage in experimental meningococcal meningitis

Cited by 30 publications

References 48 publications

Bacterial meningitis: an update of new treatment options

Bacterial meningitis: an update of new treatment options

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Virulence Traits of a Serogroup C Meningococcus and Isogenic cssA Mutant, Defective in Surface-Exposed Sialic Acid, in a Murine Model of Meningitis

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