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 language | English (US) |
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Pages (from-to) | 1-15 |
Number of pages | 15 |
Journal | Brain research |
Volume | 1060 |
Issue number | 1-2 |
DOIs | |
State | Published - Oct 26 2005 |
Externally published | Yes |
Keywords
- Calcium
- Excitotoxicity
- NMDA
- Neurodegeneration
- Nitric oxide
- mtPTP
ASJC Scopus subject areas
- Neuroscience(all)
- Molecular Biology
- Clinical Neurology
- Developmental Biology