Abstract
BackgroundPneumococcal 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.MethodsEleven-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.ResultsUpon 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).ConclusionAdjuvant 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.
Highlights
Streptococcus pneumoniae and Neisseria meningitidis are the most prevalent pathogens of childhood meningitis beyond neonatal age [1, 2]
The anti-inflammatory effect of metformin was further confirmed to be independent of serotype-specific surface polysaccharides, as metformin treatment significantly reduced the release of IL-1β, IL-6, TNF-α, and Nitric oxide (NO) after stimulation of astroglial cells with S. pneumoniae serotype 2 (D39, see Additional file 1)
These anti-inflammatory properties were further documented to be capsule-independent as metformin significantly reduced the release of IL-1β, IL-6, TNF-α, and NO to a similar extent after astroglial cell stimulation with R6—a non-encapsulated mutant of D39
Summary
Streptococcus pneumoniae and Neisseria meningitidis are the most prevalent pathogens of childhood meningitis beyond neonatal age [1, 2]. Upon recognition of the invading pathogens, recruited neutrophils together with brain-resident immune cells produce high levels of inflammatory cytokines, reactive oxygen and nitrogen species (ROS and RNS), intended to eliminate the invading pathogens and causing collateral damage to the vulnerable brain tissue [4, 15, 16] This excessive neuroinflammatory response upon pneumococcal cerebrospinal fluid (CSF) invasion together with pneumococcal toxins contributes to PM-associated central and peripheral nervous system (CNS and PNS) injury [4, 17,18,19,20]. 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. The anti-inflammatory effect of metformin was studied in primary rat astroglial cells in vitro
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