Glutamate induces hydroxyl radical formation in vivo via activation of nitric oxide synthase in Sprague–Dawley rats

Lancelot, Eric; Lecanu, Laurent; Revaud, M. L.; Boulu, R; Plotkine, Michel; Crinon, Jacques

doi:10.1016/s0304-3940(98)00095-0

Cited by 28 publications

(4 citation statements)

References 26 publications

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“…Their functional characteristics have received much attention because during neuron destruction, activated microglia have been found to represent the major source of brain immune mediators, including potentially neurotoxic pro-inflammatory cytokines and NO [27][28][29]. Microglia express TLRs.…”

Section: Discussionmentioning

confidence: 99%

Temperature- and time-dependent changes in TLR2-activated microglial NF-κB activity and concentrations of inflammatory and anti-inflammatory factors

et al. 2012

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In TLR2-activated microglia, hypothermia reduced, while hyperthermia increased, the early activation of NF-κB and the subsequent NF-κB-mediated production of TNF-α, IL-10, and NO in a time-dependent manner, suggesting that attenuation of these factors via suppression of NF-κB in microglia is one possible neuroprotective mechanism of therapeutic hypothermia. Moreover, temperature-dependent changes in microglial TNF-α production during the early phase and IL-10 and NO production during the late phase indicate that these factors might be useful as clinical markers to monitor hypothermia-related neuronal protection and hyperthermia-related neuronal injury.

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Section: Discussionmentioning

confidence: 99%

Temperature- and time-dependent changes in TLR2-activated microglial NF-κB activity and concentrations of inflammatory and anti-inflammatory factors

et al. 2012

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“…For instance, enhanced firing rates can contribute to the development of oxidative stress (Lancelot et al 1998) and will increase the load on mitochondrial metabolism (Heath and Shaw 2002), which probably plays a key role in selective motoneuron death (Kaal et al 2000). In addition, because the activity of the membrane Na/K pump is severely reduced in the spinal cord of SOD1 mice (Ellis et al 2003), increased firing rates will contribute to disturbances of the cell's ion metabolism.…”

Section: Discussionmentioning

confidence: 99%

Hyperexcitability of Cultured Spinal Motoneurons From Presymptomatic ALS Mice

Kuo

Schonewille

Siddique

et al. 2004

Journal of Neurophysiology

166

151

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of cultured spinal motoneurons from presymptomatic ALS mice. J Neurophysiol 91: 571-575, 2004. First published October 1, 2003 10.1152/jn.00665.2003. ALS (amyotrophic lateral sclerosis) is an adult-onset and deadly neurodegenerative disease characterized by a progressive and selective loss of motoneurons. Transgenic mice overexpressing a mutated human gene (G93A) coding for the enzyme SOD1 (Cu/Zn superoxide dismutase) develop a motoneuron disease resembling ALS in humans. In this generally accepted ALS model, we tested the electrophysiological properties of individual embryonic and neonatal spinal motoneurons in culture by measuring a wide range of electrical properties influencing motoneuron excitability during current clamp. There were no differences in the motoneuron resting potential, input conductance, action potential shape, or afterhyperpolarization between G93A and control motoneurons. The relationship between the motoneuron's firing frequency and injected current (f-I relation) was altered. The slope of the f-I relation and the maximal firing rate of the G93A motoneurons were much greater than in the control motoneurons. Differences in spontaneous synaptic input were excluded as a cause of increased excitability. This finding identifies a markedly elevated intrinsic electrical excitability in cultured embryonic and neonatal mutant G93A spinal motoneurons. We conclude that the observed intrinsic motoneuron hyperexcitability is induced by the SOD1 toxic gain-of-function through an aberration in the process of action potential generation. This hyperexcitability may play a crucial role in the pathogenesis of ALS as the motoneurons were cultured from presymptomatic mice.

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“…These processes are not independent, but mutually reinforcing. Reactive oxygen species are known to inhibit the reuptake of glutamate, which would result in elevated glutamate levels (Volterra, 1994; Volterra et al, 1994; Trotti et al, 1996; Bogdanov et al, 1998), whereas elevated glutamate levels induce the production of reactive oxygen species (Reynolds and Hastings, 1995; Lancelot et al, 1998). Glutamate is the major excitatory transmitter in the mammalian CNS (Fonnum, 1984; Hansson and Ronnback, 1995).…”

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confidence: 99%

Elevated Cortical Extracellular Fluid Glutamate in Transgenic Mice Expressing Human Mutant (G93A) Cu/Zn Superoxide Dismutase

Alexander

Deitch

Seeburger

et al. 2000

Journal of Neurochemistry

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Transgenic mice expressing a mutated (G93A) human Cu/Zn superoxide dismutase (SOD1) develop motor neuron pathology and clinical symptoms similar to those seen in patients with amyotrophic lateral sclerosis. Loss of motor neurons is most prominent in lumbar, followed by cervical cord and then brainstem. No significant cell death has been reported in motor cortex. The integrity of the cortical glutamate reuptake systems was evaluated using intracerebral microdialysis and western immunoblot assays for the glutamate transporters GLT-1, GLAST, and EAAC1. The basal extracellular fluid levels of aspartate, glutamate, glutamine, 3,4-dihydroxyphenylacetic acid, and 5-hydroxyindole-3-acetic acid were evaluated by HPLC. The extraction fraction of L-[ 3 H]glutamate, corrected with [ 14 C]mannitol, was also evaluated. GLT-1, EAAC1, and GLAST protein levels were determined by semiquantitative chemiluminescence immunoblot of proteins from membrane-enriched fractions. The relative optical density of film was translated into relative protein level by comparison with a standard control mouse. The SOD1 mutant mice demonstrated a significant ( p Ͻ 0.05) increase in basal levels of extracellular aspartate and glutamate. In addition, when the glutamate extraction fraction was challenged with exogenous unlabeled glutamate (500 M) by reversed microdialysis, the glutamate extraction fraction in the mutant SOD1 mice was decreased significantly from control levels. The SOD1 mutant mice demonstrated no difference in the cortical protein levels of the glutamate transporter subtypes. This study demonstrates that in areas of no visible pathology and no loss of glutamate transporter proteins, SOD1 mutant mice have elevated extracellular fluid aspartate and glutamate levels and a decreased capacity to clear glutamate from the extracellular space. Key Words: Glutamate-Reuptake-Transporter-SOD1-Amyotrophic lateral sclerosis-Mice -Microdialysis.

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Glutamate induces hydroxyl radical formation in vivo via activation of nitric oxide synthase in Sprague–Dawley rats

Cited by 28 publications

References 26 publications

Temperature- and time-dependent changes in TLR2-activated microglial NF-κB activity and concentrations of inflammatory and anti-inflammatory factors

Temperature- and time-dependent changes in TLR2-activated microglial NF-κB activity and concentrations of inflammatory and anti-inflammatory factors

Hyperexcitability of Cultured Spinal Motoneurons From Presymptomatic ALS Mice

Elevated Cortical Extracellular Fluid Glutamate in Transgenic Mice Expressing Human Mutant (G93A) Cu/Zn Superoxide Dismutase

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