c-Jun N-terminal kinase pathway inhibition in intracerebral hemorrhage.
BACKGROUND
Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG-102 (formerly D- JNKI1) induces strong neuroprotection in ischemic stroke in rodents. We investigated the effect of JNK inhibition in intracerebral hemorrhage (ICH).


METHODS
Three hours after induction of ICH by intrastriatal collagenase injection in mice, the animals received an intravenous injection of 100 microg/kg of XG-102. The neurological outcome was assessed daily and the mice were sacrificed at 6 h, 1, 2 or 5 days after ICH.


RESULTS
XG-102 administration significantly improved the neurological outcome at 1 day (p < 0.01). The lesion volume was significantly decreased after 2 days (29 +/- 11 vs. 39 +/- 5 mm(3) in vehicle-treated animals, p < 0.05). There was also a decreased hemispheric swelling (14 +/- 13 vs. 26 +/- 9% in vehicle-treated animals, p < 0.05) correlating with increased aquaporin 4 expression.


CONCLUSIONS
XG-102 attenuates cerebral edema in ICH and functional impairment at early time points. The beneficial effects observed with XG-102 in ICH, as well as in ischemic stroke, open the possibility to rapidly treat stroke patients before imaging, thereby saving precious time.
Michel-Monigadon
Delphine
D
Department of Clinical Neuroscience, Neurology Service, Centre Hospitalier Universitaire Vaudois and Lausanne University, Lausanne, Switzerland.
Bonny
Christophe
C
Hirt
Lorenz
L
D000818:Animals; D051401:Aquaporin 4 / Q000096:biosynthesis / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017364:Collagenases / Q000008:administration & dosage / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009457:Neuroglia / Q000187:drug effects; D010455:Peptides / Q000627:therapeutic use*; D004856:Postural Balance / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D010455:Peptides; D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D017364:Collagenases; C478085:D-JNKI-1