Nitric oxide synthase isoforms undertake unique roles during excitotoxicity.
OBJECTIVE
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.
Parathath
Susana R
SR
Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794-8651, USA.
Gravanis
Iordanis
I
Tsirka
Stella E
SE
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D007527:Isoenzymes / Q000502:physiology; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D007527:Isoenzymes; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D007608:Kainic Acid