Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis.

Muri, Lukas Kilian; Le, Ngoc Dung; Zemp, Jonas; Grandgirard, Denis; Leib, Stephen L. (2019). Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis. Journal of neuroinflammation, 16(1), p. 156. BioMed Central 10.1186/s12974-019-1549-6

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BACKGROUND

Pneumococcal meningitis is associated with high risk of neurological sequelae such as cognitive impairment and hearing loss. These sequelae are due to parenchymal brain and inner ear damage primarily induced by the excessive inflammatory reaction in response to bacterial brain invasion. Metformin-a biguanide drug to treat diabetes mellitus type 2-was recently found to suppress neuroinflammation and induce neuroregeneration. This study evaluated the effect of metformin adjunctive to antibiotics on neuroinflammation, brain and inner ear damage, and neurofunctional outcome in experimental pediatric pneumococcal meningitis.

METHODS

Eleven-day-old Wistar rats were infected intracisternally with 5.22 ± 1.27 × 103 CFU Streptococcus pneumoniae and randomized for treatment with metformin (50 mg/kg, i.p., once daily for 3 weeks) plus ceftriaxone (100 mg/kg, i.p., bid, n = 61) or ceftriaxone monotherapy (n = 79). Cortical damage and hippocampal apoptosis were evaluated histomorphometrically 42 h post infection. Cerebrospinal fluid cytokine levels were analyzed during acute infection. Five weeks post infection, auditory brainstem responses were measured to determine hearing thresholds. Spiral ganglion neuron density and abundance of recently proliferated and integrated hippocampal granule neurons were assessed histologically. Additionally, the anti-inflammatory effect of metformin was studied in primary rat astroglial cells in vitro.

RESULTS

Upon pneumococcal infection, metformin treatment significantly reduced levels of inflammatory cytokines and nitric oxide production in cerebrospinal fluid and in astroglial cell cultures in vitro (p < 0.05). Compared to animals receiving ceftriaxone monotherapy, adjunctive metformin significantly reduced cortical necrosis (p < 0.02) during acute infection and improved median click-induced hearing thresholds (60 dB vs. 100 dB, p < 0.002) 5 weeks after infection. Adjuvant metformin significantly improved pure tone hearing thresholds at all assessed frequencies compared to ceftriaxone monotherapy (p < 0.05) and protected from PM-induced spiral ganglion neuron loss in the inner ear (p < 0.05).

CONCLUSION

Adjuvant metformin reduces brain injury during pneumococcal meningitis by decreasing the excessive neuroinflammatory response. Furthermore, it protects spiral ganglion neurons in the inner ear and improves hearing impairments after experimental pneumococcal meningitis. These results identify adjuvant metformin as a promising therapeutic option to improve the outcome after pediatric pneumococcal meningitis.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Clinical Microbiology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Muri, Lukas Kilian; Le, Ngoc Dung; Zemp, Jonas; Grandgirard, Denis 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] This work was supported by a grant from the Swiss National Science Foundation (Grant 310030-162583).

Language:

English

Submitter:

Stephen Leib

Date Deposited:

20 Sep 2019 10:28

Last Modified:

04 Nov 2019 05:45

Publisher DOI:

10.1186/s12974-019-1549-6

PubMed ID:

31351490

Uncontrolled Keywords:

Brain injury Inner ear damage Metformin Neuroinflammation Neurologic sequelae Neuroregeneration Pneumococcal meningitis

BORIS DOI:

10.7892/boris.133327

URI:

https://boris.unibe.ch/id/eprint/133327

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