Reduced spiral ganglion neuronal loss by adjunctive neurotrophin-3 in experimental pneumococcal meningitis

Demel, Cornelia; Hoegen, Tobias; Giese, Armin; Angele, Barbara; Pfister, Hans‐Walter; Koedel, Uwe; Klein, Matthias

doi:10.1186/1742-2094-8-7

Cited by 30 publications

(25 citation statements)

References 55 publications

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“…This is very similar to the mortality seen in humans in central Europe (2,3). Furthermore, we previously found that adjunctive dexamethasone significantly decreased hearing loss and its morphological correlates in the model of pneumococcal meningitis that was used here (34). Likewise, such a positive otoprotective effect of dexamethasone has been shown in adult patients with pneumococcal meningitis (39).…”

Section: Discussionsupporting

confidence: 56%

“…Dexamethasone, which was shown to be effective in human patients in central Europe (3,44), was of benefit not only in mice but also in meningitis models using adult rats, rabbits, and gerbils (34,(45)(46)(47). Nevertheless, even though dexamethasone seems of relatively strong benefit in these studies, its positive effect seems limited to patients treated in developed countries (39).…”

Section: Discussionmentioning

confidence: 91%

“…If compared with the data on dexamethasone in meningitis, the effect of NAC seems rather low: dexamethasone reduced hearing loss (for click, 1-kHz, and 10-kHz stimuli) and decreased the loss of spiral ganglion neuronal cells in the model that was also used in this study (34). Dexamethasone, which was shown to be effective in human patients in central Europe (3,44), was of benefit not only in mice but also in meningitis models using adult rats, rabbits, and gerbils (34,(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

“…(i) Clinical score. Animals were investigated clinically before infection and 18 h, 24 h, 42 h, 66 h, and 2 weeks after infection, and clinical scores (CS) were determined as previously described (34)(35)(36), ranging from 0 points if there were no clinically noticeable signs of disease to 12 points if the animal died. In brief, the following criteria were assessed: (i) beam balancing, (ii) postural reflexes, (iii) piloerection, (iv) epileptic seizures, and (v) level of consciousness.…”

Section: Methodsmentioning

confidence: 99%

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Adjunctive N -Acetyl- l -Cysteine in Treatment of Murine Pneumococcal Meningitis

Högen

Demel

Giese

et al. 2013

Antimicrob Agents Chemother

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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...

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Adjunctive N -Acetyl- l -Cysteine in Treatment of Murine Pneumococcal Meningitis

Högen

Demel

Giese

et al. 2013

Antimicrob Agents Chemother

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“…Additionally, the capability of ceftriaxone to reduce inflammation and apoptosis has been recently demonstrated. 30 Considering the Leung groups's experimental findings in an animal model of PD 6 and our data on the molecular interaction between ceftriaxone and α-synuclein, we thought to study the in vitro effects of ceftriaxone on viability and α-synuclein expression of PC12 cells exposed to 6-OHDA. Indeed, it is known that the treatment of neural cells with 6-OHDA reduces cell viability, 31 induces apoptosis, 32−34 and increases α-synuclein immunoreactivity.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Ceftriaxone Blocks the Polymerization of α-Synuclein and Exerts Neuroprotective Effects in Vitro

Ruzza¹,

Siligardi

Hussain

et al. 2013

ACS Chem. Neurosci.

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ABSTRACT:The β-lactam antibiotic ceftriaxone was suggested as a therapeutic agent in several neurodegenerative disorders, either for its ability to counteract glutamate-mediated toxicity, as in cerebral ischemia, or for its ability to enhance the degradation of misfolded proteins, as in Alexander's disease. Recently, the efficacy of ceftriaxone in neuroprotection of dopaminergic neurons in a rat model of Parkinson's disease was documented. However, which characteristics of ceftriaxone mediate its therapeutic effects remains unclear. Since, at the molecular level, neuronal α-synuclein inclusions and pathological α-synuclein transmission play a leading role in initiation of Parkinson-like neurodegeneration, we thought of investigating, by circular dichroism spectroscopy, the capability of ceftriaxone to interact with α-synuclein. We found that ceftriaxone binds with good affinity to α-synuclein and blocks its in vitro polymerization. Considering this finding, we also documented that ceftriaxone exerts neuroprotective action in an in vitro model of Parkinson's disease. Our data, in addition to the findings on neuroprotective activity of ceftriaxone on Parkinson-like neurodegeneration in vivo, indicates ceftriaxone as a potential agent in treatment of Parkinson's disease.

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Histopathological changes to the peripheral vestibular system following meningitic labyrinthitis

Pauna

Knoll

Lubner

et al. 2020

Laryngoscope Investig Oto

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Objective: While cochlear ossification is a common sequela of meningitic labyrinthitis, less is known about the effects of meningitis on the peripheral vestibular end organs. Herein, we investigate histopathologic changes in the peripheral vestibular system and cochlea in patients with a history of meningitic labyrinthitis. Methods: Temporal bone (TB) specimens from patients with a history of meningitis were evaluated and compared to age-matched controls. Specimens were evaluated by light microscopy and assessed for qualitative changes, including the presence of vestibular and/or cochlear endolymphatic hydrops, presence and location of inflammatory cells, new bone formation, and labyrinthitis ossificans; and quantitative changes, including Scarpa's ganglion neuron (ScGN) and spiral ganglion neuron (SGN) counts.Results: Fifteen TBs from 10 individuals met inclusion and exclusion criteria. Presence of inflammatory cells and fibrous tissue was found in 5 TBs. Of these, evidence of labyrinthitis ossificans was found in 2 TBs. In the peripheral vestibular system, mild to severe degeneration of the vestibular membranous labyrinth was identified in 60% of cases (n = 9 TBs). There was a 21.2% decrease (range, 3%-64%) in the mean total count of ScGN in patients with meningitis, compared to age-matched controls. In the cochlea, there was a 45% decrease (range, 25.3%-80.9%) in the mean total count of SGN compared to age-matched controls (n = 14 TBs). Conclusions: Otopathologic analysis of TBs from patients with a history of meningitic labyrinthitis demonstrated distinct peripheral vestibular changes. Future research may help to delineate potential mechanisms for the observed otopathologic changes following meningitis. Level of Evidence: N/A K E Y W O R D S meningitis, otopathology, Scarpa ganglion neurons, spiral ganglion neurons, temporal bone, vestibular changes

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Reduced spiral ganglion neuronal loss by adjunctive neurotrophin-3 in experimental pneumococcal meningitis

Cited by 30 publications

References 55 publications

Adjunctive N -Acetyl- l -Cysteine in Treatment of Murine Pneumococcal Meningitis

Adjunctive N -Acetyl- l -Cysteine in Treatment of Murine Pneumococcal Meningitis

Ceftriaxone Blocks the Polymerization of α-Synuclein and Exerts Neuroprotective Effects in Vitro

Histopathological changes to the peripheral vestibular system following meningitic labyrinthitis

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