Inhibition of Src tyrosine kinase and effect on outcomes in a new in vivo model of surgically induced brain injury.
OBJECTIVE
Brain tissue at the periphery of a neurosurgical resection site is vulnerable to injury by a variety of mechanisms including direct trauma, edema, hemorrhage, retractor stretch, and electrocautery. The goal in the present study was to develop an in vivo model of surgically induced brain injury and to test an Src tyrosine kinase inhibitor for neuroprotective properties in this model.


METHODS
The authors developed a new surgically induced brain injury model in rats. This model involves resection of part of the frontal lobe. Sprague-Dawley male rats weighing between 300 and 350 g were divided randomly into four groups: Group 1, surgical injury with vehicle treatment; Group 2, surgical injury after treatment with PP1 (an Src tyrosine kinase inhibitor with known neuroprotective properties); Group 3, sham surgery; and Group 4, control. Postoperative assessment included blood-brain barrier (BBB) permeability studies, and histological, immunohistochemical, and Western blot analyses. The authors found that surgical injury caused localized edema and disruption of the BBB compared with findings in the sham surgery group. Treatment with PP1 was associated with decreased edema, decreased breakdown of the BBB, decreased expression of both vascular endothelial growth factor and phosphorylated extracellular signal-regulated kinase 1 and 2, and preservation of ZO-1 expression.


CONCLUSIONS
In this study the authors describe a simple and reproducible in vivo animal model of surgically induced brain injury. Pretreatment with PP1 results in improved outcomes in this model, which suggests a possible role for Src tyrosine kinase inhibitors as preoperative therapy for planned neurosurgical procedures.
Jadhav
Vikram
V
Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, California 92354, USA.
Matchett
Gerald
G
Hsu
Frank P K
FP
Zhang
John H
JH
D000818:Animals; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D001930:Brain Injuries / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D008297:Male; D019635:Neurosurgical Procedures / Q000009:adverse effects*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D011720:Pyrazoles; D011743:Pyrimidines; D019061:src-Family Kinases