SRC kinase inhibition improves acute outcomes after experimental intracerebral hemorrhage.
OBJECTIVE
The mechanisms by which intracerebral hemorrhages produce changes of blood flow and metabolism, cell death, and behavioral abnormalities are complex. In this study, we begin to test the hypothesis that intracerebral hemorrhage activates Src kinases that phosphorylate other molecules to produce cell injury and behavioral deficits after intracerebral hemorrhage (ICH).


METHODS
ICH was produced in adult Sprague Dawley rats by direct injection of autologous blood (50 microL) into striatum. Src kinase activity, glucose hypermetabolic areas around the ICH, TUNEL-stained cells, and apomorphine-induced rotational behaviors were assessed in animals with ICH pretreated with the Src kinase inhibitor, PP1, or with vehicle.


RESULTS
PP1 (3 mg/kg) blocked increases of Src kinase activity (5-fold) at 3 hours after ICH. PP1 also blocked the areas of glucose hypermetabolism and decreased the numbers of TUNEL-stained cells surrounding the ICH at 24 hours. Finally, apomorphine-induced (1 mg/kg) rotation at 24 hours after ICH was markedly attenuated by previous treatment with PP1 (3 mg/kg intraperitoneal).


CONCLUSIONS
PP1 decreases Src kinase activation, glucose metabolic activation, cell death, and behavioral abnormalities after ICH in striatum of adult rats. It is hypothesized that intracerebral hemorrhage, possibly via thrombin activation of protease-activated receptors, activates Src that phosphorylates NMDA receptors, matrix metalloproteinases, and other proteins that mediate injury after ICH.
Ardizzone
Timothy D
TD
Medical Investigation of Neurodevelopmental Diseases Institute and Department of Neurology, University of California at Davis Medical Center, Sacramento, CA 95817, USA.
Zhan
Xinhua
X
Ander
Brad P
BP
Sharp
Frank R
FR
D000818:Animals; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D016896:Treatment Outcome; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D019061:src-Family Kinases