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 [Ca 2+] i responses differentially. [Ca 2+] i transients, assessed by the fluorescent cytosolic Ca 2+ 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 [Ca 2+] 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 [Ca 2+] i rises, whereby the duration of [Ca 2+] 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 [Ca 2+] 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 [Ca 2+] i sequestration are causally involved.
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