Delayed inhibition of c-Jun N-terminal kinase worsens outcomes after focal cerebral ischemia.
The stress-activated protein kinase c-Jun N-terminal kinase (JNK) is a central regulator in neuronal death cascades. In animal models of cerebral ischemia, acute inhibition of JNK reduces infarction and improves outcomes. Recently however, emerging data suggest that many neuronal death mediators may have biphasic properties-deleterious in the acute stage but potentially beneficial in the delayed stage. Here, we hypothesized that JNK may also have biphasic actions, so some caution may be required in the development of JNK inhibitors for stroke. Sprague Dawley rats underwent 90 min transient occlusions of the middle cerebral artery. Acute treatment (10 min poststroke) with the JNK inhibitor SP600125 reduced infarction volumes. In contrast, delayed treatment (7 d poststroke) worsened infarction volumes and neurological outcomes. Immunostaining of peri-infarct cortex showed that JNK inhibition suppressed surrogate markers of neurovascular remodeling, including matrix metalloproteinase-9 in GFAP-positive astrocytes and microvascular density. Consistent with these in vivo data, SP600125 significantly suppressed in vitro angiogenesis in rat brain endothelial cultures. Our data provide initial proof-of-concept that the neuronal death target JNK may also participate in endogenous processes of neurovascular remodeling and recovery after cerebral ischemia.
Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02129, USA.
Yoshihiro
Y
Murata
Norio
N
Fujiwara
Ji Hae
JH
Seo
Feng
F
Yan
Xiangrong
X
Liu
Yasukazu
Y
Terasaki
Yumin
Y
Luo
Ken
K
Arai
Xunming
X
Ji
Eng H
EH
Lo
D000818:Animals; D000873:Anthracenes / Q000008:administration & dosage / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000873:Anthracenes; D004791:Enzyme Inhibitors; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9