Role of c-Jun N-terminal kinase in cerebral vasospasm after experimental subarachnoid hemorrhage.
OBJECTIVE
Inflammation could play a role in cerebral vasospasm after subarachnoid hemorrhage (SAH). SP600125 a c-Jun N-terminal kinase (JNK) inhibitor reduces inflammation. The present study examined if SP600125 could reduce cerebral vasospasm.


METHODS
Twenty-seven dogs were assigned to 5 groups: control, SAH, SAH plus dimethyl sulfoxide (DMSO), SAH plus SP600125 (10 micromol/L), and SAH plus SP600125 (30 micromol/L). SAH was induced by the injection of autologous blood into the cisterna magna on day 0 and day 2. Angiograms were evaluated on day 0 and day 7. The behavior of the dogs was evaluated daily. The activation of the JNK pathway, the infiltration of leukocytes, and the production of cytokines were also evaluated.


RESULTS
Severe vasospasm was observed in the basilar artery of SAH and DMSO dogs. The JNK signaling pathway was activated in the basilar artery after SAH and SP600125 reduced angiographic and morphological vasospasm and improved behavior scores with a concomitant reduction of infiltrated leukocytes and IL-6 production.


CONCLUSIONS
These results demonstrate that SP600125 attenuated cerebral vasospasm through a suppressed inflammatory response, which may provide a novel therapeutic target for cerebral vasospasm.
Yatsushige
Hiroshi
H
Department of Physiology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Yamaguchi
Mitsuo
M
Zhou
Changman
C
Calvert
John W
JW
Zhang
John H
JH
D000792:Angiography; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006470:Hemorrhage; D007150:Immunohistochemistry; D007249:Inflammation; D015850:Interleukin-6 / Q000096:biosynthesis / Q000134:cerebrospinal fluid / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D007962:Leukocytes / Q000166:cytology; D010766:Phosphorylation; D015398:Signal Transduction; D013345:Subarachnoid Hemorrhage / Q000473:pathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020301:Vasospasm, Intracranial / Q000201:enzymology*
D000873:Anthracenes; D016207:Cytokines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D004121:Dimethyl Sulfoxide