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.