The c-Jun N-terminal kinase (JNK) inhibitor XG-102 enhances the neuroprotection of hyperbaric oxygen after cerebral ischaemia in adult rats.
OBJECTIVE
Both hyperbaric oxygenation (HBO) and inhibition of the c-Jun N-terminal kinases (JNKs) by the peptide inhibitor XG-102 (D-JNKI-1) are efficient protective strategies against ischaemia-induced neurodegeneration. The present study investigated whether the combination of HBO and JNK inhibitor, XG-102, provides additive neuroprotection against cerebral ischaemia.


METHODS
Rat middle cerebral artery was occluded (MCAO) for 90 min. XG-102 [2 mg/kg, intraperitoneally] or HBO (3 ATA, 60 min) was applied 3 h after the onset of MCAO. For the combination treatment, HBO was started 10 min after the injection of XG-102. Twenty-four hours after MCAO, the infarct area, the neurological score and the immunohistochemistry staining in brain slices for cleaved-PARP, transferase-mediated biotinylated UTP nick end labelling, c-Jun and phosphorylated (activated) c-Jun were observed.


RESULTS
XG-102 or HBO alone reduced the total infarct area by 43% and 63%, respectively. The combination diminished total infarct area by 78%, improved the neurological function and reduced brain oedema. Co-application of HBO and XG-102 also significantly reduced the cleavage of PARP, by 96% and 91% in cortical penumbra and ischaemic core, respectively. Moreover, cotreatment significantly attenuated the number of cells labelled with transferase-mediated biotinylated UTP nick end labelling and phosphorylated c-Jun.


CONCLUSIONS
Our study demonstrates that HBO reinforces the efficiency of neuroprotective drugs such as XG-102 and vice versa. Both treatments, physical HBO and pharmacological XG-102, are already in phase I/II studies and promising strategies for clinical use.
Department of Neurology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
J-R
JR
Liu
Y
Y
Zhao
A
A
Patzer
N
N
Staak
R
R
Boehm
G
G
Deuschl
J
J
Culman
C
C
Bonny
T
T
Herdegen
C
C
Eschenfelder
D000375:Aging; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology / Q000628:therapy; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology / Q000628:therapy; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006931:Hyperbaric Oxygenation / Q000379:methods*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010455:Peptides; D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases; C478085:D-JNKI-1