Thrombin-induced ischemic tolerance is prevented by inhibiting c-jun N-terminal kinase.
We have studied ischemic tolerance induced by the serine protease thrombin in two different models of experimental ischemia. In organotypic hippocampal slice cultures, we demonstrate that incubation with low doses of thrombin protects neurons against a subsequent severe oxygen and glucose deprivation. L-JNKI1, a highly specific c-jun N-terminal kinase (JNK) inhibitor, and a second specific JNK inhibitor, SP600125, prevented thrombin preconditioning (TPC). We also show that the exposure to thrombin increases the level of phosphorylated c-jun, the major substrate of JNK. TPC, in vivo, leads to significantly smaller lesion sizes after a 30-min middle cerebral artery occlusion (MCAo), and the preconditioned mice were better off in the three tests used to evaluate functional recovery. In accordance with in vitro results, TPC in vivo was prevented by administration of L-JNKI1, supporting a role for JNK in TPC. These results, from two different TPC models and with two distinct JNK inhibitors, show that JNK is likely to be involved in TPC.
Granziera
Cristina
C
Service de Neurologie, CHUV, Lausanne, Switzerland.
Thevenet
Jonathan
J
Price
Melanie
M
Wiegler
Karine
K
Magistretti
Pierre J
PJ
Badaut
Jérôme
J
Hirt
Lorenz
L
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology* / Q000503:physiopathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000503:physiopathology; D019194:Ischemic Preconditioning / Q000379:methods*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000378:metabolism* / Q000494:pharmacology
D000873:Anthracenes; D004791:Enzyme Inhibitors; D016755:Proto-Oncogene Proteins c-jun; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D013917:Thrombin