Combined effect of non-bacteriolytic antibiotic and inhibition of matrix metalloproteinases prevents brain injury and preserves learning, memory and hearing function in experimental paediatric pneumococcal meningitis.

Muri, Lukas; Grandgirard, Denis; Buri, Michelle; Perny, Michael; Leib, Stephen (2018). Combined effect of non-bacteriolytic antibiotic and inhibition of matrix metalloproteinases prevents brain injury and preserves learning, memory and hearing function in experimental paediatric pneumococcal meningitis. Journal of neuroinflammation, 15(1), p. 233. BioMed Central 10.1186/s12974-018-1272-8

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BACKGROUND Pneumococcal meningitis is associated with high mortality and morbidity rates. Up to 50% of survivors show neurologic sequelae including hearing loss, cognitive impairments and learning disabilities, being particularly detrimental in affected infants and children where adjuvant therapy with dexamethasone has no proven beneficial effect. We evaluated the effect of concomitantly targeting specific pathophysiological mechanisms responsible for brain damage-i.e. matrix-metalloproteinase (MMP) activity and the exacerbated cerebral inflammation provoked through antibiotic-induced bacterial lysis. Here, we combined adjunctive therapies previously shown to be neuroprotective when used as single adjuvant therapies. METHODS Eleven-day-old Wistar rats were infected intracisternally with 6.44 ± 2.17 × 10 CFU Streptococcus pneumoniae and randomised for treatment with ceftriaxone combined with (a) single adjuvant therapy with daptomycin (n = 24), (b) single adjuvant therapy with Trocade (n = 24), (c) combined adjuvant therapy (n = 66) consisting of daptomycin and Trocade, or (d) ceftriaxone monotherapy (n = 42). Clinical parameters and inflammatory CSF cytokine levels were determined during acute meningitis. Cortical damage and hippocampal apoptosis were assessed 42 h after infection. Morris water maze and auditory brainstem responses were used to assess neurofunctional outcome 3 weeks after infection. RESULTS We found significantly reduced apoptosis in the hippocampal subgranular zone in infant rats receiving adjuvant Trocade (p < 0.01) or combined adjuvant therapy (p < 0.001). Cortical necrosis was significantly reduced in rats treated with adjuvant daptomycin (p < 0.05) or combined adjuvant therapy (p < 0.05) compared to ceftriaxone monotherapy. Six hours after treatment initiation, CSF cytokine levels were significantly reduced for TNF-α (p < 0.01), IL-1β (p < 0.01), IL-6 (p < 0.001) and IL-10 (p < 0.01) in animals receiving combined adjuvant intervention compared to ceftriaxone monotherapy. Importantly, combined adjuvant therapy significantly improved learning and memory performance in infected animals and reduced hearing loss (77.14 dB vs 60.92 dB, p < 0.05) by preserving low frequency hearing capacity, compared to ceftriaxone monotherapy. CONCLUSION Combined adjuvant therapy with the non-bacteriolytic antibiotic daptomycin and the MMP inhibitor Trocade integrates the neuroprotective effects of both single adjuvants in experimental paediatric pneumococcal meningitis by reducing neuroinflammation and brain damage, thereby improving neurofunctional outcome. This strategy represents a promising therapeutic option to improve the outcome of paediatric patients suffering from pneumococcal meningitis.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Infectiology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Muri, Lukas Kilian; Grandgirard, Denis; Buri, Michelle; Perny, Michael and Leib, Stephen

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1742-2094

Publisher:

BioMed Central

Funders:

[4] Swiss National Science Foundation

Projects:

[UNSPECIFIED] http://p3.snf.ch/Project-162583

Language:

English

Submitter:

Stephen Leib

Date Deposited:

27 Aug 2018 11:56

Last Modified:

23 Oct 2019 13:53

Publisher DOI:

10.1186/s12974-018-1272-8

PubMed ID:

30131074

Uncontrolled Keywords:

Brain injury Combined adjuvant therapy Hearing loss Neuroinflammation Neurologic sequelae Pneumococcal meningitis

BORIS DOI:

10.7892/boris.119599

URI:

https://boris.unibe.ch/id/eprint/119599

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