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 4

tPA-induced early preconditioning.

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tPA-induced early preconditioning. (A) Mean cell survival in hippocampal...
(A) Mean cell survival in hippocampal neurons treated with either tPA (in nM) or with itPA followed by exposure to OGD conditions during 55 minutes. n = 20 for each observation. Error bars denote SD. *P < 0.05 compared with untreated cells; **P < 0.05 compared with untreated neurons and with cells treated with 500 nM tPA. (B and C) Mean hippocampal neuronal survival following exposure to OGD conditions (55 minutes) and incubation with 1 μM tPA alone or in combination with either α2-antiplasmin (AP, 140 nM) or RAP (100 nM) or with either one of the NMDAR antagonists MK-801 (10 μM) or DL-AP5 (50 μM) or with plasmin alone (Pl; 100 nM) or with RAP alone. n = 20 in B and n = 15 in C. Error bars denote SD. In B: *P < 0.05 compared with cells left untreated; **P < 0.05 compared with cells kept under OGD conditions; ***P < 0.05 compared with neurons maintained under OGD conditions and with tPA alone. In C: *P < 0.05 compared with cells maintained under OGD conditions and either left untreated or incubated with MK-801 or DL-AP5 alone. (D) Mean neuronal survival following incubation with 250 μM KA either alone or in combination with 1 μM tPA. *P < 0.05 compared with untreated cells. n = 10. Error bars denote SD in all panels. “PREC.” (preconditioning) indicates the moment when cells were incubated with each compound.