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 8

IPC increases tPA activity and plasminogen expression in the hippocampal CA1 layer.

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IPC increases tPA activity and plasminogen expression in the hippocampal...
(A) Representative example of cerebral perfusion changes in the hippocampus during preconditioning with 3 episodes of BCCAO of 1-minute duration, each separated by 5-minute intervals of normal perfusion. (B and C) Representative in situ zymography assay in WT and tPA–/– mice immediately after 3 episodes of BCCAO performed as described in A. Note the presence of tPA activity in the hippocampal CA1 layer (white arrows in B). (D and E) Cresyl violet staining in the hippocampal CA1 layer of WT (D) and tPA–/– (E) mice 48 hours after 3 episodes of intermittent BCCAO. Note the absence of cell death despite a significant increase in tPA activity in the same hippocampal area as in WT mice. (F and G) Immunoreactivity for plasminogen in the CA1 layer of WT mice before (F) and after (G) IPC. Blue is DAPI, green is plasminogen. Original magnification, ×4 (B and C) and ×40 (D–G).