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 3

Effect of tPA on neuronal survival.

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Effect of tPA on neuronal survival. (A and D) Mean increase in enzymatic...
(A and D) Mean increase in enzymatically active tPA in the media of hippocampal (A) and cortical (D) neurons exposed to OGD conditions for 0–60 minutes. Error bars denote SD. n = 12. *P < 0.05 compared with controls maintained under normoxia. The insets are magnifications of the first 5 minutes of each curve. (B and E) Mean reduction in cell survival in hippocampal (B) and cortical neurons (E) 24 hours after incubation with 0–1 μM tPA under normoxic conditions. Error bars denote SD. n = 10. *P < 0.05 compared with untreated cells (white bar). (C and F) Mean decrease in cell survival in WT (white bars) and tPA deficient (tPA–/–; black bars) hippocampal (C) and cortical (F) neurons exposed to 55 minutes of OGD conditions or kept under normoxic conditions (no OGD). A subgroup of neurons was incubated with 1 μM tPA (+ tPA). Error bars denote SD. n = 10 for each observation. In C: *P < 0.05 compared with cells kept under normoxic conditions; **P < 0.05 compared with neurons maintained under OGD conditions without tPA. In F: *P < 0.05 compared with WT cells maintained under OGD conditions without tPA or with WT and tPA–/– neurons maintained under OGD conditions and treated with tPA; **P < 0.05 compared with WT and tPA–/– neurons maintained under OGD conditions without tPA.