Journal Article

Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis

Grandgirard, Denis, Leib, Stephen L., Le, Ngoc Dung, Zemp, Jonas, Muri, Lukas

2019

Overview

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 × 10 3  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.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Animals / Anti-Bacterial Agents - administration & dosage / Anti-Bacterial Agents - therapeutic use / Apoptosis - drug effects / Bacterial meningitis / Biomedical and Life Sciences / Biomedicine / Brain injuries / Brain injury / Ceftriaxone - administration & dosage / Ceftriaxone - therapeutic use / Cytokines - cerebrospinal fluid / Disease Models, Animal / Drug therapy / Drug Therapy, Combination / Hearing loss / Hearing Loss - cerebrospinal fluid / Hearing Loss - drug therapy / Hippocampus - drug effects / Immunology / Inner ear damage / Meningitis, Pneumococcal - cerebrospinal fluid / Meningitis, Pneumococcal - drug therapy / Metformin / Metformin - administration & dosage / Metformin - therapeutic use / Neurobiology / Neuroinflammation / Neurologic sequelae / Neurology / Neurons - drug effects / Neuroprotective agents / Neuroprotective Agents - administration & dosage / Neuroprotective Agents - therapeutic use / Neurosciences / Pneumococcal meningitis / Prevention / Rats / Rats, Wistar / Spiral Ganglion - drug effects / Testing / Treatment Outcome