Role of c-Jun N-terminal kinase in early brain injury after subarachnoid hemorrhage.
The c-Jun N-terminal kinase (JNK) is induced by cerebral ischemia and injurious blood components acutely after subarachnoid hemorrhage (SAH). We hypothesized that inhibition of JNK will prevent damage to the neurovascular unit in the early brain injury period after SAH. Ninety-nine male SD rats (300-350 g) were randomly assigned to sham, SAH, and SAH treated with JNK inhibitor groups. SAH was induced by endovascular perforation. The JNK inhibitor SP600125 was administered intraperitoneally at 1 hr before and 6 hr after SAH. At 24 hr after SAH, we observed increased phosphorylation of JNK and c-Jun. Signs of neurovascular damage were observed in the hemorrhagic brains; these included the increases of aquaporin (AQP)-1 expression and brain water content as well as enhanced matrix metalloproteinase (MMP)-9 activity, vascular collagen IV loss, increased VEGF tissue level, and Evans blue extravasation. The appearances of cleaved caspase-3 expression, TUNEL-positive cells, and apoptotic morphology in cerebral tissues were associated with neurological deficit after SAH. JNK inhibition prevented c-Jun phosphorylation and suppressed AQP1, MMP-9, VEGF, and caspase-3 activation, with concomitant diminution of neuronal injury, blood-brain barrier preservation, reduced brain swelling, and improved neurological deficit in rats after SAH. This study demonstrates a multitude of beneficial effects of JNK inhibition, including protection of the neurovascular unit in early brain injury after SAH.
Yatsushige
Hiroshi
H
Department of Physiology, Loma Linda University, Loma Linda, California 92354, USA.
Ostrowski
Robert P
RP
Tsubokawa
Tamiji
T
Colohan
Austin
A
Zhang
John H
JH
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051398:Aquaporin 1 / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000473:pathology; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D001930:Brain Injuries / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D053148:Caspase 3 / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D004487:Edema / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D024141:Collagen Type IV; D016755:Proto-Oncogene Proteins c-jun; D042461:Vascular Endothelial Growth Factor A; D051398:Aquaporin 1; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9