Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis
Abstract 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 in...
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-019-1549-6 |
| _version_ | 1818260615049773056 |
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| author | Lukas Muri Ngoc Dung Le Jonas Zemp Denis Grandgirard Stephen L. Leib |
| author_facet | Lukas Muri Ngoc Dung Le Jonas Zemp Denis Grandgirard Stephen L. Leib |
| author_sort | Lukas Muri |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-12T18:34:09Z |
| format | Article |
| id | doaj.art-41f13a51d7c3461e8599a33658a311ee |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-12T18:34:09Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-41f13a51d7c3461e8599a33658a311ee2022-12-22T00:15:51ZengBMCJournal of Neuroinflammation1742-20942019-07-0116111410.1186/s12974-019-1549-6Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitisLukas Muri0Ngoc Dung Le1Jonas Zemp2Denis Grandgirard3Stephen L. Leib4Neuroinfection Laboratory, Institute for Infectious Diseases, University of BernNeuroinfection Laboratory, Institute for Infectious Diseases, University of BernNeuroinfection Laboratory, Institute for Infectious Diseases, University of BernNeuroinfection Laboratory, Institute for Infectious Diseases, University of BernNeuroinfection Laboratory, Institute for Infectious Diseases, University of BernAbstract 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.http://link.springer.com/article/10.1186/s12974-019-1549-6Pneumococcal meningitisBrain injuryNeuroinflammationNeurologic sequelaeMetforminInner ear damage |
| spellingShingle | Lukas Muri Ngoc Dung Le Jonas Zemp Denis Grandgirard Stephen L. Leib Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis Journal of Neuroinflammation Pneumococcal meningitis Brain injury Neuroinflammation Neurologic sequelae Metformin Inner ear damage |
| title | Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis |
| title_full | Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis |
| title_fullStr | Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis |
| title_full_unstemmed | Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis |
| title_short | Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis |
| title_sort | metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis |
| topic | Pneumococcal meningitis Brain injury Neuroinflammation Neurologic sequelae Metformin Inner ear damage |
| url | http://link.springer.com/article/10.1186/s12974-019-1549-6 |
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