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.
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Authors | Osvaldo Mirante, Melanie Price, Wilfredo Puentes, Ximena Castillo, Corinne Benakis, Jonathan Thevenet, Denis Monard, Lorenz Hirt |
Journal | International journal of molecular sciences
(Int J Mol Sci)
Vol. 14
Issue 8
Pg. 16719-31
(Aug 14 2013)
ISSN: 1422-0067 [Electronic] Switzerland |
PMID | 23949634
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- L-JNKI-1
- Peptides
- Serpin E2
- JNK Mitogen-Activated Protein Kinases
- Thrombin
- Glucose
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Topics |
- Animals
- Brain
(metabolism)
- Brain Ischemia
(metabolism)
- Cell Death
- Cell Hypoxia
(physiology)
- Gene Knock-In Techniques
- Glucose
(deficiency, metabolism)
- Hippocampus
(metabolism)
- JNK Mitogen-Activated Protein Kinases
(antagonists & inhibitors)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neurons
(metabolism)
- Peptides
(pharmacology)
- Rats
- Rats, Sprague-Dawley
- Serpin E2
(deficiency, genetics, metabolism)
- Stroke
(metabolism)
- Thrombin
(antagonists & inhibitors, metabolism)
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