Signaling pathways for early brain injury after subarachnoid hemorrhage.
Few studies have examined the signaling pathways that contribute to early brain injury after subarachnoid hemorrhage (SAH). Using a rat SAH model, the authors explored the role of vascular endothelial growth factor (VEGF) and mitogen-activation protein kinase (MAPK) in early brain injury. Male Sprague-Dawley rats (n = 172) weighing 300 to 350 g were used for the experimental SAH model, which was induced by puncturing the bifurcation of the left anterior cerebral and middle cerebral arteries. The blood-brain barrier (BBB), brain edema, intracranial pressure, and mortality were evaluated at 24 hours after SAH. The phosphorylation of VEGF and different MAPK subgroups (ERK1/2, p38, and JNK) were examined in both the cortex and the major cerebral arteries. Experimental SAH increased intracranial pressure, BBB permeability, and brain edema and produced high mortality. SAH induced phosphorylation of VEGF and MAPKs in the cerebral arteries and, to a lesser degree, in the cortex. PP1, an Src-family kinase inhibitor, reduced BBB permeability, brain edema, and mortality and decreased the phosphorylation of VEGF and MAPKs. The authors conclude that VEGF contributes to early brain injury after SAH by enhancing the activation of the MAPK pathways, and that the inhibition of these pathways might offer new treatment strategies for SAH.
Kusaka
Gen
G
Department of Neurosurgery, Louisiana State University Health Sciences Center in Shreveport, Shreveport, Louisiana 71130-3932, USA.
Ishikawa
Mami
M
Nanda
Anil
A
Granger
D Neil
DN
Zhang
John H
JH
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D015153:Blotting, Western; D001929:Brain Edema / Q000209:etiology / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000503:physiopathology*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007427:Intracranial Pressure / Q000187:drug effects / Q000502:physiology; D008297:Male; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D019061:src-Family Kinases / Q000096:biosynthesis / Q000187:drug effects
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases