Damage to Neurons in Culture Following Medium Change: Role of Glutamine and Extracellular Generation of Glutamate

Driscoll, Bernard F.; Deibler, Gladys E.; Law, Mona J.; Crane, Alison M.

doi:10.1111/j.1471-4159.1993.tb09818.x

Cited by 53 publications

(29 citation statements)

References 14 publications

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“…13 In the present study, S. intermedius and S. aureus produced ammonia at high concentrations in vitro, but seemed to do so along somewhat different pathways. Within the first 4 hours of incubation, S. intermedius primarily used arginine as a source of ammonia.…”

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confidence: 83%

Toxic levels of ammonia in human brain abscess

Dahlberg¹,

Ivanović²,

Hassel

2016

JNS

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obJective Brain abscesses could lead to cerebral symptoms through tissue destruction, edema, changes in brain architecture, and increased intracranial pressure. However, the possibility that the pus itself could contribute to symptoms has received little attention. Brain abscesses are areas of tissue destruction, proteolysis, and formation of free amino acids, which are energy substrates for bacteria and possible sources of ammonia. Ammonia is neurotoxic, may cause brain edema, and could contribute to the symptoms of brain abscesses. methods The authors analyzed the extracellular phase of pus from 14 patients with brain abscesses with respect to ammonia and amino acids. For comparison, CSF from 10 patients undergoing external ventricular drainage was included. The ammonia-forming ability of Streptococcus intermedius and Staphylococcus aureus, two common microbial isolates in brain abscesses, was studied in vitro. results In brain abscesses ammonia was 15.5 mmol/L (median value; range 1.7-69.2 mmol/L). In CSF ammonia was 29 µmol/L (range 17-55 µmol/L; difference from value in pus: p < 0.001). The total concentration of amino acids in brain abscesses was 1.12-16 times higher than the ammonia concentration (p = 0.011). The median glucose value in pus was 0 mmol/L (range 0-2.1 mmol/L), lactate was 21 mmol/L (range 3.3-26.5 mmol/L), and pH was 6.8 (range 6.2-7.3). In vitro, S. intermedius and S. aureus formed ammonia at 6-7 mmol/L in 24 hours when incubated with 20 proteinogenic amino acids plus g-aminobutyric acid (GABA), taurine, and glutathione at 1 mmol/L. coNclusioNs Intracerebral abscesses contain toxic levels of ammonia. At the concentrations found in pus, ammonia could contribute to the brain edema and the symptoms of brain abscesses.

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confidence: 83%

Toxic levels of ammonia in human brain abscess

Dahlberg¹,

Ivanović²,

Hassel

2016

JNS

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“…Complete changes of the feeding medium were performed daily for 4 days (between days 5 and 8 in vitro) to induce NMDA receptor-mediated excitotoxic damage to the cultures (Driscoll et al, 1991(Driscoll et al, , 1993Mytilineou et al, 1997). Selegiline and DMS were added only during medium changes (days 5-9 in vitro).…”

Section: Resultsmentioning

confidence: 99%

l‐(−)‐Desmethylselegiline, a Metabolite of Selegiline [l‐(−)‐Deprenyl], Protects Mesencephalic Dopamine Neurons from Excitotoxicity In Vitro

Mytilineou

Radcliffe

Olanow

1997

Journal of Neurochemistry

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Selegiline [L-(-)-deprenyl], a monoamine oxidase B inhibitor, has been used in the treatment of Parkinson's disease as a putative neuroprotective agent. Selegiline is metabolized rapidly in the gastrointestinal tract and liver to desmethylselegiline (DMS) and methamphetamine. We have previously shown that selegiline protects dopamine neurons in mesencephalic cultures from toxicity resulting from activation of glutamate receptors. In the present study we examined whether DMS has similar neuroprotective effects. Our data show that DMS protects dopamine neurons from N-methyl-o-aspartate receptor-mediated excitotoxic damage. The efficacy of DMS is greater than that of selegiline, as it can cause protection at lower concentrations and provide significantly greater levels of protection at the same concentrations. Our results suggest that DMS might be the active compound responsible for the neuroprotective properties of selegiline. Key Words: Parkinson's disease-Selegiline-LDeprenyl -Desmethylselegiline -Excitotoxicity -Neuroprotection. J. Neurochem. 68, 434-436 (1997)., in doses of 10 mg/day, is a relatively selective inhibitor of monoamine oxidase (MAO) B. As an adjunct to levodopa therapy, selegiline has been shown to provide improved function and reduced motor fluctuations in patients with advanced Parkinson's disease (PD) (Birkmayer and Riederer, 1984;Golbe et al., 1988). Greater interest has centered on selegiline as a putative neuroprotective therapy based on its capacity to block the development of MPTP-induced parkinsonism (Cohen et al., 1984;Heikkila et al., 1984) and oxidative stress secondary to the MAO-B-dependent metabolism of dopamine (Cohen and Spina, 1989;Olanow, 1992). In patients with early untreated PD, controlled clinical trials demonstrated that selegiline delays the emergence of disability necessitating the introduction of levodopa therapy (Tetrud and Langston, 1989; Parkinson Study Group, 1989, l993a) and slows the progression of signs and symptoms (Olanow et al., 1995). Until recently, it has been considered that the benefits of selegiline in PD are due to its capacity to inhibit MAO-B. However, recent laboratory studies have shown that selegiline prevents neuronal degeneration in various in vivo and in vitro experimental models (Mytilineou and Cohen, 1985; Tatton and Geenwood, 1991;Salo and Tatton, 1992;Ansari et al., 1993;Roy and Bedard, 1993), through a mechanism that does not depend on inhibition ofMAO-B activity (Ansari et al., 1993;Mytilineou et al., 1997).In humans and experimental animals, selegiline is rapidly metabolized in the gastrointestinal tract and liver to L-desmethylselegiline (DMS) and L-methamphetamineby the cytochrome P-450 enzyme system (Yoshida et al., 1986;Heinonen et al., 1994;Barrett et al., 1996). DMS is an inhibitor of MAO-B, but it is less potent than selegiline in in vitro and in vivo assays (Borbe et al., 1990).Our recent studies have shown that selegiline protects cultured mesencephalic dopamine (DA) neurons from cell death caused by N-methyl-D-asparta...

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“…L-glutamine is known to be easily converted into L-glutamate by chemical degradation. 25 Thus, high basal activity in the β-lactamase assay using CHO-NFAT-bla-hmGluR1b could be at least partially due to activation of mGluR1 mediated by L-glutamate generated from the degradation of L-glutamine. Even in the absence of L-glutamine, the mGluR1 antagonist, compound 1, inhibited β-lactamase activity below the basal level in CHO-NFAT-bla-hmGluR1b.…”

Section: Discussionmentioning

confidence: 99%