The c-Jun N-terminal kinase (JNK) inhibitor XG-102 enhances the neuroprotection of hyperbaric oxygen after cerebral ischaemia in adult rats

J‐R. Liu, Y. Zhao, A. Patzer, N. Staak, R. Boehm, G. Deuschl, J. Culman, C. Bonny, T. Herdegen and C. Eschenfelder (2010) Neuropathology and Applied Neurobiology36, 211–224
The c‐Jun N‐terminal kinase (JNK) inhibitor XG‐102 enhances the neuroprotection of hyperbaric oxygen after cerebral ischaemia i...

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Published in:Neuropathology and applied neurobiology 2010-04, Vol.36 (3), p.211-224
Main Authors: Liu, J-R., Zhao, Y., Patzer, A., Staak, N., Boehm, R., Deuschl, G., Culman, J., Bonny, C., Herdegen, T., Eschenfelder, C.
Format: Article
Language:English
Subjects:
Aging
Animals
Biological and medical sciences
Brain - drug effects
Brain - metabolism
Brain - pathology
Brain Edema - drug therapy
Brain Edema - pathology
Brain Edema - therapy
Brain Ischemia - drug therapy
Brain Ischemia - pathology
Brain Ischemia - therapy
c-Jun N-terminal kinase
cerebral ischaemia
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - therapeutic use
Human mycoses
hyperbaric oxygen
Hyperbaric Oxygenation - methods
Infarction, Middle Cerebral Artery - drug therapy
Infarction, Middle Cerebral Artery - pathology
Infarction, Middle Cerebral Artery - therapy
Infectious diseases
JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors
Male
Medical sciences
middle cerebral artery
Mycoses
Mycoses of the nervous system
neurodegeneration
Neurology
neuroprotection
Neuroprotective Agents - administration & dosage
Neuroprotective Agents - therapeutic use
Peptides - administration & dosage
Peptides - therapeutic use
Phosphorylation
Proto-Oncogene Proteins c-jun - metabolism
Random Allocation
Rats
Rats, Sprague-Dawley
Time Factors
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Summary:J‐R. Liu, Y. Zhao, A. Patzer, N. Staak, R. Boehm, G. Deuschl, J. Culman, C. Bonny, T. Herdegen and C. Eschenfelder (2010) Neuropathology and Applied Neurobiology36, 211–224
The c‐Jun N‐terminal kinase (JNK) inhibitor XG‐102 enhances the neuroprotection of hyperbaric oxygen after cerebral ischaemia in adult rats Aim: 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. Conclusion: 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.
ISSN:0305-1846
1365-2990
DOI:10.1111/j.1365-2990.2009.01047.x