Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus.
The best-known function of the serine protease tissue-type plasminogen activator (tPA) is as a thrombolytic enzyme. However, it is also found in structures of the brain that are highly vulnerable to hypoxia-induced cell death, where its association with neuronal survival is poorly understood. Here, we have demonstrated that hippocampal areas of the mouse brain lacking tPA activity are more vulnerable to neuronal death following an ischemic insult. We found that sublethal hypoxia, which elicits tolerance to subsequent lethal hypoxic/ischemic injury in a natural process known as ischemic preconditioning (IPC), induced a rapid release of neuronal tPA. Treatment of hippocampal neurons with tPA induced tolerance against a lethal hypoxic insult applied either immediately following insult (early IPC) or 24 hours later (delayed IPC). tPA-induced early IPC was independent of the proteolytic activity of tPA and required the engagement of a member of the LDL receptor family. In contrast, tPA-induced delayed IPC required the proteolytic activity of tPA and was mediated by plasmin, the NMDA receptor, and PKB phosphorylation. We also found that IPC in vivo increased tPA activity in the cornu ammonis area 1 (CA1) layer and Akt phosphorylation in the hippocampus, as well as ischemic tolerance in wild-type but not tPA- or plasminogen-deficient mice. These data show that tPA can act as an endogenous neuroprotectant in the murine hippocampus.
Echeverry
Ramiro
R
Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Wu
Jialing
J
Haile
Woldeab B
WB
Guzman
Johanna
J
Yepes
Manuel
M
D000818:Animals; D001921:Brain / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D005341:Fibrinolysin; D005343:Fibrinolytic Agents / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D010960:Plasminogen Activators / Q000378:metabolism / Q000494:pharmacology*; D057057:Serine Proteases / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology
D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D057057:Serine Proteases; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator