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 9

Effect of tPA deficiency in an in vivo model of delayed IPC.

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Effect of tPA deficiency in an in vivo model of delayed IPC. (A–F). Repr...
(A–F). Representative images of cresyl violet staining through the dorsal hippocampus of WT, tPA–/–, and Plg–/– mice 72 hours after 20 minutes of BCCAO without (– IPC) and with (+ IPC) IPC performed 24 hours earlier as described in Methods. Original magnification, ×20. (G) Mean score of hippocampal damage in WT, tPA–/–, and Plg–/– mice 72 hours after 20 minutes of BCCAO without (–) or with (+) IPC 24 hours earlier. n = 8–10 observations. *P < 0.05 compared with preconditioned WT mice. (H) Representative Western blot analysis for Akt phosphorylated at serine 473 (pAkt) in WT, tPA–/–, and Plg–/– mice 0, 1, 6, and 24 hours after IPC performed as described in Figure 8. Lanes were run on the same gel but were noncontiguous.