Nitric oxide applications prior and simultaneous to potentially excitotoxic NMDA-evoked calcium transients

Cell death or survival

Aileen Schröter, Shaida A. Andrabi, Gerald Wolf, Thomas F W Horn

Research output: Contribution to journalArticle

Abstract

Nitric oxide (NO) is a molecule that plays a prominent role in neurotoxic as well as neuroprotective pathways. Here, we investigated the effects of NO on potentially excitotoxic glutamate-induced intracellular calcium ([Ca 2+]i) dynamics. Our hypothesis was that pre- and coexposure to NO in conjunction with glutamate receptor stimulation modulates [Ca2+]i responses differentially. [Ca2+] i transients, assessed by the fluorescent cytosolic Ca2+ indicator dye fluo-4, were elicited in mouse striatal neurons by consecutive NMDA applications (200 μM for 100 s each). Subgroups of neuronal cultures were additionally exposed to a NO donor (S-nitroso-N-acetyl-d,l-penicillamine, SNAP, 50-500 μM), either by pre- (for 6 h prior to NMDA) or cotreatment (for 30 min during NMDA). Pretreatment with NO led to dramatically decreased NMDA-evoked [Ca2+]i rises in comparison to controls (NMDA alone). Annexin V/propidium iodide staining showed consistently that NO pretreatment is protective against NMDA-induced cell death. In contrast, NO/NMDA cotreatment caused a potentiation of [Ca2+]i rises, whereby the duration of [Ca2+]i transients following NMDA application was prolonged and remained at an increased plateau level. Simultaneous application of the mitochondrial permeability transition pore (mtPTP) blocker cyclosporin A (2 μM) during the NO/NMDA cotreatment prevented the deregulation of [Ca2+]i. The observed [Ca 2+]i deregulation was accompanied by a decrease in the mitochondrial membrane potential as indicated by tetramethylrhodamine methylester (TMRM) fluorescence. These findings suggest that NO can act in a protective way due to preconditioning or can have a possibly detrimental impact in case of acute release. They provide a possible explanation for the ambivalence of NO in neurodegenerative processes where glutamate receptor stimulation and mitochondrial [Ca2+]i sequestration are causally involved.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalBrain Research
Volume1060
Issue number1-2
DOIs
StatePublished - Oct 26 2005
Externally publishedYes

Fingerprint

N-Methylaspartate
Cell Survival
Nitric Oxide
Cell Death
Calcium
Glutamate Receptors
Corpus Striatum
Penicillamine
Nitric Oxide Donors
Propidium
Mitochondrial Membrane Potential
Annexin A5
Cyclosporine
Glutamic Acid
Coloring Agents
Fluorescence
Staining and Labeling
Neurons

Keywords

  • Calcium
  • Excitotoxicity
  • mtPTP
  • Neurodegeneration
  • Nitric oxide
  • NMDA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Nitric oxide applications prior and simultaneous to potentially excitotoxic NMDA-evoked calcium transients : Cell death or survival. / Schröter, Aileen; Andrabi, Shaida A.; Wolf, Gerald; Horn, Thomas F W.

In: Brain Research, Vol. 1060, No. 1-2, 26.10.2005, p. 1-15.

Research output: Contribution to journalArticle

Schröter, Aileen ; Andrabi, Shaida A. ; Wolf, Gerald ; Horn, Thomas F W. / Nitric oxide applications prior and simultaneous to potentially excitotoxic NMDA-evoked calcium transients : Cell death or survival. In: Brain Research. 2005 ; Vol. 1060, No. 1-2. pp. 1-15.
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AB - Nitric oxide (NO) is a molecule that plays a prominent role in neurotoxic as well as neuroprotective pathways. Here, we investigated the effects of NO on potentially excitotoxic glutamate-induced intracellular calcium ([Ca 2+]i) dynamics. Our hypothesis was that pre- and coexposure to NO in conjunction with glutamate receptor stimulation modulates [Ca2+]i responses differentially. [Ca2+] i transients, assessed by the fluorescent cytosolic Ca2+ indicator dye fluo-4, were elicited in mouse striatal neurons by consecutive NMDA applications (200 μM for 100 s each). Subgroups of neuronal cultures were additionally exposed to a NO donor (S-nitroso-N-acetyl-d,l-penicillamine, SNAP, 50-500 μM), either by pre- (for 6 h prior to NMDA) or cotreatment (for 30 min during NMDA). Pretreatment with NO led to dramatically decreased NMDA-evoked [Ca2+]i rises in comparison to controls (NMDA alone). Annexin V/propidium iodide staining showed consistently that NO pretreatment is protective against NMDA-induced cell death. In contrast, NO/NMDA cotreatment caused a potentiation of [Ca2+]i rises, whereby the duration of [Ca2+]i transients following NMDA application was prolonged and remained at an increased plateau level. Simultaneous application of the mitochondrial permeability transition pore (mtPTP) blocker cyclosporin A (2 μM) during the NO/NMDA cotreatment prevented the deregulation of [Ca2+]i. The observed [Ca 2+]i deregulation was accompanied by a decrease in the mitochondrial membrane potential as indicated by tetramethylrhodamine methylester (TMRM) fluorescence. These findings suggest that NO can act in a protective way due to preconditioning or can have a possibly detrimental impact in case of acute release. They provide a possible explanation for the ambivalence of NO in neurodegenerative processes where glutamate receptor stimulation and mitochondrial [Ca2+]i sequestration are causally involved.

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