Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus
Ramiro Echeverry, … , Johanna Guzman, Manuel Yepes
Ramiro Echeverry, … , Johanna Guzman, Manuel Yepes
Published May 3, 2010
Citation Information: J Clin Invest. 2010;120(6):2194-2205. https://doi.org/10.1172/JCI41722.
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Research Article Neuroscience

Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus

Abstract

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.

Authors

Ramiro Echeverry, Jialing Wu, Woldeab B. Haile, Johanna Guzman, Manuel Yepes

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Figure 7

Endogenous tPA induces delayed hypoxic preconditioning.

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Endogenous tPA induces delayed hypoxic preconditioning. (A) Mean neurona...
(A) Mean neuronal survival in WT and tPA–/– neurons preconditioned with sublethal OGD conditions for 30 minutes, followed 24 hours later by exposure to lethal OGD (55 minutes). n = 12–15. *P < 0.05 compared with WT neurons maintained under normoxic conditions; **P < 0.05 compared with non-preconditioned neurons; ***P < 0.05 compared with tPA–/– cells maintained under normoxia. (B) Mean neuronal survival in WT neurons preconditioned with sublethal OGD in the presence of 140 nM α2-antiplasmin, 1.4 μM aprotinin, 20 mM EACA, 10 μM MK-801, 20 nM wortmannin (Wort), or 100 nM RAP. n = 6–10. *P < 0.05 compared with non-preconditioned cells; **P < 0.05 compared with all preconditioned cells. (C) Mean neuronal survival in tPA–/– neurons preconditioned with sublethal OGD in the presence of 60 nM tPA or with a combination of tPA and 10 μM MK-801, tPA and 20 nM wortmannin, or tPA and 100 nM RAP, followed 24 hours by a lethal hypoxic injury (55 minutes of OGD). Error bars denote SD. n = 8–10. *P < 0.05 compared with untreated preconditioned cells; **P < 0.05 compared with cells preconditioned in the presence of tPA.