Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice.
Stroke and many neurodegenerative diseases culminate in neuronal death through a mechanism known as excitotoxicity. Excitotoxicity proceeds through a complex signaling pathway that includes the participation of the serine protease tissue plasminogen activator (tPA). tPA mediates neurotoxic effects on resident central nervous system cells as well alters blood-brain barrier (BBB) permeability, which further promotes neurodegeneration. Another signaling molecule that promotes neurodegeneration and BBB dysfunction is nitric oxide (NO), although its precise role in pathological progression remains unclear. We examine here the potentially interrelated roles of tPA, NO and peroxynitrite (ONOO-), which is the toxic metabolite of NO, in BBB breakdown and neurodegeneration following intrahippocampal injection of the glutamate analog kainite (KA). We find that NO and ONOO- production are linked to tPA-mediated excitotoxic injury, and demonstrate that NO provision suffices to restore the toxic effects of KA in tPA-deficient mice that are normally resistant to excitotoxicity. NO also promotes BBB breakdown and excitotoxicity. Interestingly, BBB breakdown in itself does not suffice to elicit neurodegeneration; a subsequent ONOO(-)-mediated event is required. In conclusion, NO and ONOO- function as downstream effectors of tPA-mediated excitotoxicity.
Parathath
Susana R
SR
Program in Molecular and Cellular Biology, Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA.
Parathath
Saj
S
Tsirka
Stella E
SE
D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology* / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid / Q000008:administration & dosage / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009498:Neurotoxins / Q000008:administration & dosage / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D018690:Excitatory Amino Acid Agonists; C093285:NOC 18; D009498:Neurotoxins; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010959:Tissue Plasminogen Activator; D007608:Kainic Acid