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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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 1

Relationship between tPA activity and hippocampal cell death.

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Relationship between tPA activity and hippocampal cell death. (A–L) Repr...
(A–L) Representative pictures of cresyl violet staining and in situ zymography assays of the dorsal hippocampus of WT mice under normoxic conditions (A–D) or of WT and tPA-deficient (tPA–/–) mice 72 hours after 20 minutes of BCCAO (E–L). Note the presence of cell death in areas devoid of tPA activity in WT (CA1 layer, G) and tPA–/– mice (CA1-CA2 and CA3 layers; I, K, and L). Original magnification, ×4 (A, B, E, F, I, and J) and ×20 (C, D, G, H, K, and L). (M–X) Representative pictures of DAPI, Fluoro-Jade, and TUNEL staining in the CA1 layer of WT mice under normoxic conditions (M–P) or of WT and tPA–/– mice 5 days after 20 minutes of BCCAO (Q–X). Note the presence of widespread necrotic changes, neurodegeneration, and apoptotic cell death in both WT (Q–T) and tPA–/– mice (U–X). Blue is DAPI, and green is Fluoro-Jade (N, R, and V) or TUNEL (P, T, and X). Original magnification, ×40 (M–X).