Nitric Oxide Synthase Isoforms Undertake Unique Roles During Excitotoxicity

Abstract

Background and Purpose-Excitotoxicity is a component of many neurodegenerative diseases. The signaling events that lead from excitotoxic injury to neuronal death remain incompletely defined. Pharmacological approaches have shown that nitric oxide production is critical for the progression of neurodegeneration after the initiation of excitotoxicity by the glutamate analog kainate. Although nitric oxide additionally triggers blood-brain barrier (BBB) breakdown, the breakdown does not in itself inevitably lead to neuronal cell death, because neuroprotective pharmacological means can be used subsequently to prevent the neural death. Methods-In this study, we use a genetic approach to analyze the contribution of 3 nitric oxide synthase (NOS) isoforms, neuronal NOS, endothelial NOS, and inducible NOS, to neurodegeneration and BBB breakdown in this setting. Results-We find that neuronal NOS is critical for the progression of kainate-stimulated neurodegeneration, whereas endothelial NOS is required only for BBB breakdown. Inducible NOS is not required for either event. Conclusions-The observation that endothelial NOS-deficient mice undergo excitotoxic neurodegeneration in the absence of BBB breakdown unlinks the two processes. These findings suggest that it may be possible to achieve full amelioration of excitotoxic-triggered neurodegeneration through developing isoform-specific inhibitors solely for neuronal NOS.

Targeted knock-down of neuronal nitric oxide synthase expression in basal forebrain with RNA interference

“…Under conditions of excessive activation of the NMDA receptor, NO synthesized in the cytosol by the action of nNOS may initiate both cytosolic and nuclear apoptotic signaling (Garthwaite et al, 1989;Dawson et al, 1991;Bonfoco et al, 1996). As recently shown by us (Koliatsos et al, 2004;Zhou et al, 2006;Zhou et al, 2007) and others (Corso et al, 1997;Parathath et al, 2007), similar processes can be signaled between neurons, i.e. nNOS-expressing interneurons can provide the source of NO that can diffuse and initiate apoptotic cascades in adjacent projection neurons.…”

In the eye of the storm: mitochondrial damage during heart and brain ischaemia

“…Glutamate can induce the death of some neurons via stimulation of nNOS . Genetic knockout of nNOS or iNOS protects against ischaemic brain damage, whereas knockout of eNOS is detrimental, presumably because the latter mediates vasodilatation .…”

Nitric Oxide (No), Citrulline - No Cycle Enzymes, Glutamine Synthetase and Oxidative Stress in Anoxia (Hypobaric Hypoxia) and Reperfusion in Rat Brain

“…Each route is likely activated and propagated through selective transmembrane and intracellular signaling system 39. One of the events triggered by excessive glutamate release and relevant to excitotoxicity is the production of NO 40. NO synthesis is activated cerebrovascular diseases by release of glutamate combined with inhibition of glutamate removal, which leads to NMDA receptor over activation and excess Ca 2+ influx 41.…”