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Endogenous Protease Nexin-1 Protects against Cerebral Ischemia
Stroke Laboratory, Neurology Service, Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois and Lausanne University, Lausanne 1011, Switzerland
Friedrich Miescher Institute for Biomedical Research, Basel 4058, Switzerland
* Author to whom correspondence should be addressed.
Received: 1 July 2013; in revised form: 31 July 2013 / Accepted: 1 August 2013 / Published: 14 August 2013
Abstract: The serine protease thrombin plays a role in signalling ischemic neuronal death in the brain. Paradoxically, endogenous neuroprotective mechanisms can be triggered by preconditioning with thrombin (thrombin preconditioning, TPC), leading to tolerance to cerebral ischemia. Here we studied the role of thrombin’s endogenous potent inhibitor, protease nexin-1 (PN-1), in ischemia and in tolerance to cerebral ischemia induced by TPC. Cerebral ischemia was modelled in vitro in organotypic hippocampal slice cultures from rats or genetically engineered mice lacking PN-1 or with the reporter gene lacZ knocked into the PN-1 locus PN-1HAPN-1-lacZ/HAPN-1-lacZ (PN-1 KI) exposed to oxygen and glucose deprivation (OGD). We observed increased thrombin enzyme activity in culture homogenates 24 h after OGD. Lack of PN-1 increased neuronal death in the CA1, suggesting that endogenous PN-1 inhibits thrombin-induced neuronal damage after ischemia. OGD enhanced β-galactosidase activity, reflecting PN-1 expression, at one and 24 h, most strikingly in the stratum radiatum, a glial cell layer adjacent to the CA1 layer of ischemia sensitive neurons. TPC, 24 h before OGD, additionally increased PN-1 expression 1 h after OGD, compared to OGD alone. TPC failed to induce tolerance in cultures from PN-1−/− mice confirming PN-1 as an important TPC target. PN-1 upregulation after TPC was blocked by the c-Jun N-terminal kinase (JNK) inhibitor, L-JNKI1, known to block TPC. This work suggests that PN-1 is an endogenous neuroprotectant in cerebral ischemia and a potential target for neuroprotection.
Keywords: protease nexin-1; thrombin preconditioning; cerebral ischemia; organotypic hippocampal slice cultures; glucose and oxygen deprivation; c-Jun N-terminal kinase; stroke; neuroprotection
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Mirante, O.; Price, M.; Puentes, W.; Castillo, X.; Benakis, C.; Thevenet, J.; Monard, D.; Hirt, L. Endogenous Protease Nexin-1 Protects against Cerebral Ischemia. Int. J. Mol. Sci. 2013, 14, 16719-16731.
Mirante O, Price M, Puentes W, Castillo X, Benakis C, Thevenet J, Monard D, Hirt L. Endogenous Protease Nexin-1 Protects against Cerebral Ischemia. International Journal of Molecular Sciences. 2013; 14(8):16719-16731.
Mirante, Osvaldo; Price, Melanie; Puentes, Wilfredo; Castillo, Ximena; Benakis, Corinne; Thevenet, Jonathan; Monard, Denis; Hirt, Lorenz. 2013. "Endogenous Protease Nexin-1 Protects against Cerebral Ischemia." Int. J. Mol. Sci. 14, no. 8: 16719-16731.