D-JNKI1, a cell-penetrating c-Jun-N-terminal kinase inhibitor, protects against cell death in severe cerebral ischemia.
OBJECTIVE
In 2 models of severe ischemic injury, we have evaluated the neuroprotective action of D-JNKI1, a cell-penetrating and protease-resistant peptide selectively inhibiting the c-Jun-N-terminal kinase (JNK).


METHODS
Hippocampal slices from newborn rats were subjected to oxygen (5%) and glucose (1 mmol/L) deprivation for 30 minutes. Cell death was evaluated with propidium iodide, and the evoked potential responses were recorded in the CA1 region after stimulation in CA3. Male ICR-CD1 mice were subjected to permanent endoluminal "suture" middle cerebral artery occlusion (MCAo). The lesion size was determined after 24 hours by triphenyl-tetrazolium chloride staining, and neurological scores and rotarod treadmill performance were used to evaluate the neurological outcome.


RESULTS
In vitro, D-JNKI administration 6 hours after oxygen glucose deprivation reduced cell death at 24 hours from 21%+/-8% (n=10) to 5%+/-3% (n=7, P<0.01). This protective effect was still seen at 48 hours, paralleled by an improved amplitude of the evoked potential response. In vivo in the mouse, D-JNKI1 administration 3 hours after ischemia significantly reduced the infarct volume from 162+/-27 mm(3) (n=14) to 85+/-27 mm(3) (n=9, P<0.001). The functional outcome was also improved.


CONCLUSIONS
JNK inhibition prevents cell death induced by oxygen and glucose deprivation in hippocampal slice cultures in vitro and by permanent suture MCAo in vivo. D-JNKI1 is a powerful neuroprotectant in models of both mild and severe cerebral ischemia, with an extended therapeutic window. Further investigations are needed to identify the relevant JNK target(s) mediating ischemic neuronal death.
Hirt
Lorenz
L
Service de Neurologie, CHUV, Lausanne, Switzerland. Lorenz.Hirt@chuv.hospvd.ch
Badaut
Jérôme
J
Thevenet
Jonathan
J
Granziera
Cristina
C
Regli
Luca
L
Maurer
Fabienne
F
Bonny
Christophe
C
Bogousslavsky
Julien
J
D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects*; D003470:Culture Media; D005947:Glucose; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D051379:Mice; D023421:Models, Animal; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen; D010455:Peptides / Q000494:pharmacology*; D011597:Psychomotor Performance; D051381:Rats
D003470:Culture Media; D018696:Neuroprotective Agents; D010455:Peptides; C478085:D-JNKI-1; D005947:Glucose; D010100:Oxygen