BackgroundHearing loss is a frequent long-term complication of pneumococcal meningitis (PM). Its main pathological correlate is damage to the organ of Corti and loss of spiral ganglion neurons. The only current treatment option is cochlear implants which require surviving neurons. Here, we investigated the impact of systemically applied neurotrophin-3 (NT-3) on long-term hearing loss and the survival of neurons.MethodsEighteen hours after infection with S. pneumoniae, C57BL/6 mice were treated with a combination of ceftriaxone with NT-3 or dexamethasone or placebo. Hearing, cochlear damage, and brain damage were assessed by audiometry and histology.ResultsThe main findings from immunohistochemical visualization of neurotrophins (NT-3, BDNF) and their receptors (TrkB, TrkC, and p75) in the cochlea were (i) enhanced staining for the cell survival-promoting receptor TrkB and (ii) increased NT-3 staining in NT-3 treated mice, showing that systemically applied NT-3 reaches the cochlea. The major effects of adjunctive NT-3 treatment were (i) a reduction of meningitis-induced hearing impairment and (ii) a reduction of spiral ganglion neuronal loss. The efficacy of NT-3 therapy was comparable to that of dexamethasone.ConclusionSystemically applied NT-3 might be an interesting candidate to improve hearing outcome after pneumococcal meningitis.

Hearing impairment is a common and frequently permanent sequel of Streptococcus suis meningitis in humans. Nevertheless, mechanisms underlying the development of cochlear damage have not been addressed so far. In the present work, we characterized a mouse model of suppurative labyrinthitis and meningitis induced by a systemic infection with S. suis and studied the impact of the injected bacterial dosage on the progression of such inflammatory events. We observed that high infection doses of bacteria lead to sustained bacteremia, with an increase in the permeability of the blood-labyrinth and blood-brain barriers, causing suppurative labyrinthitis and meningitis, respectively. However, in mice infected with a low dose of S. suis, bacteria disappeared quickly from blood, hence, cochlear inflammation and meningitis were not consistent features. This model of S. suis infection seems ideal to evaluate novel drugs that may help alleviate the negative consequences of such important sequelae of S. suis-induced meningitis and labyrinthitis.

Despite antibiotic therapy, acute and long-term complications are still frequent in pneumococcal meningitis. One important trigger of these complications is oxidative stress, and adjunctive antioxidant treatment with N-acetyl-L-cysteine was suggested to be protective in experimental pneumococcal meningitis. However, studies of effects on neurological long-term sequelae are limited. Here, we investigated the impact of adjunctive N-acetyl-L-cysteine on long-term neurological deficits in a mouse model of meningitis. C57BL/6 mice were intracisternally infected with Streptococcus pneumoniae. Eighteen hours after infection, mice were treated with a combination of ceftriaxone and placebo or ceftriaxone and N-acetyl-L-cysteine, respectively. Two weeks after infection, neurologic deficits were assessed using a clinical score, an open field test (explorative activity), a t-maze test (memory function), and auditory brain stem responses (hearing loss). Furthermore, cochlear histomorphological correlates of hearing loss were assessed. Adjunctive N-acetyl-L-cysteine reduced hearing loss after pneumococcal meningitis, but the effect was minor. There was no significant benefit of adjunctive N-acetyl-L-cysteine treatment in regard to other long-term complications of pneumococcal meningitis. Cochlear morphological correlates of meningitis-associated hearing loss were not reduced by adjunctive N-acetyl-L-cysteine. In conclusion, adjunctive therapy with N-acetyl-L-cysteine at a dosage of 300 mg/kg of body weight intraperitoneally for 4 days reduced hearing loss but not other neurologic deficits after pneumococcal meningitis in mice. These results make a clinical therapeutic benefit of N-acetyl-L-cysteine in the treatment of patients with pneumococcal meningitis questionable. Streptococcus pneumoniae is the most common etiological agent of bacterial meningitis in adults in the United States and Europe (1). Despite advanced antibiotic therapy and supportive intensive care, it still has a high case fatality rate of about 20% (2, 3). This unfavorable clinical outcome is often caused by intracranial and systemic complications, such as brain edema, hydrocephalus, cerebrovascular complications, and intracranial hemorrhage. Up to 50% of survivors suffer from long-term deficits, such as hearing loss (2, 4, 5). One reason for the development of acute and longterm intracranial and cochlear complications is collateral tissue damage from the host's own immune response, which is meant to fight the invasive pathogen. Activated immune cells and neutrophils that invade the subarachnoid space produce massive amounts of reactive oxygen (ROS) and nitrogen species (RNS), including superoxide anion (O 2 Ϫ ) and nitric oxide (NO) (6). The simultaneous production of O 2 Ϫ and NO leads to the formation of peroxynitrite (ONOO Ϫ ). ROS, RNS, and especially ONOO Ϫ can exert a variety of toxic actions, including lipid peroxidation (which leads to endothelial cell dysfunction), DNA strand breakage [followed by poly(ADP-ribose) polymerase (PARP) activation and s...