The JNK inhibitor XG-102 protects from ischemic damage with delayed intravenous administration also in the presence of recombinant tissue plasminogen activator.
BACKGROUND
XG-102 (formerly D-JNKI1), a TAT-coupled dextrogyre peptide which selectively inhibits the c-Jun N-terminal kinase, is a powerful neuroprotectant in mouse models of middle cerebral artery occlusion (MCAo) with delayed intracerebroventricular injection. We aimed to determine whether this neuroprotection could also be achieved by intravenous injection of XG-102, which is a more feasible approach for future use in stroke patients. We also tested the compatibility of the compound with recombinant tissue plasminogen activator (rtPA), commonly used for intravenous thrombolysis and known to enhance excitotoxicity.


METHODS
Male ICR-CD1 mice were subjected to a 30-min-suture MCAo. XG-102 was injected intravenously in a single dose, 6 h after ischemia. Hippocampal slice cultures were subjected to oxygen (5%) and glucose (1 mM) deprivation for 30 min. rtPA was added after ischemia and before XG-102 administration, both in vitro and in vivo.


RESULTS
The lowest intravenous dose achieving neuroprotection was 0.0003 mg/kg, which reduced the infarct volume after 48 h from 62 +/- 19 mm(3) (n = 18) for the vehicle-treated group to 18 +/- 9 mm(3) (n = 5, p < 0.01). The behavioral outcome was also significantly improved at two doses. Addition of rtPA after ischemia enhanced the ischemic damage both in vitro and in vivo, but XG-102 was still able to induce a significant neuroprotection.


CONCLUSIONS
A single intravenous administration of XG-102 several hours after ischemia induces a powerful neuroprotection. XG-102 protects from ischemic damage in the presence of rtPA. The feasibility of systemic administration of this promising compound and its compatibility with rtPA are important steps for its development as a drug candidate in ischemic stroke.
Wiegler
Karine
K
Service de Neurologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Suisse.
Bonny
Christophe
C
Coquoz
Didier
D
Hirt
Lorenz
L
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009924:Organ Culture Techniques; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D010455:Peptides; D011994:Recombinant Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D010959:Tissue Plasminogen Activator; C478085:D-JNKI-1