Effect of pretreatment with a tyrosine kinase inhibitor (PP1) on brain oedema and neurological function in an automated cortical cryoinjury model in mice

Abstract

Cerebral oedema is a significant cause of morbidity in neurosurgical practice. To our knowledge, there is no ideal drug for prevention or treatment of brain oedema. Based on the current understanding of the pathogenesis of brain oedema, tyrosine kinase inhibitors could have a role in reducing brain oedema but preclinical studies are needed to assess their effectiveness. We evaluated the role of pretreatment with 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine (PP1), an Src tyrosine kinase inhibitor, in reducing cerebral oedema and preserving neurological function measured 24hours after an automated cortical cryoinjury in mice. Sixteen adult male Swiss albino mice were subjected to an automated cortical cryoinjury using a dry ice-acetone mixture. The experimental group (n=8) received an intraperitoneal injection of PP1 dissolved in dimethyl sulfoxide (DMSO) at a dose of 1.5mg/kg body weight 45minutes prior to the injury. The control group (n=8) received an intraperitoneal injection of DMSO alone. A further eight mice underwent sham injury. The animals were evaluated using the neurological severity score (NSS) at 24hours post-injury, after which the animals were sacrificed and their brains removed, weighed, dehydrated for 48hours and weighed again. The percentage of brain water content was calculated as: {[(wet weight - dry weight)/wet weight] × 100}. The mean (standard deviation, SD) NSS was 11.7 (1.8) in the experimental group and 10.5 (1.3) in the control group (p=0.15). The mean (SD) percentage water content of the brain was 78.6% (1.3%) in the experimental group and 77.2% (1.1%) in the control group (p=0.03). The percentage water content in the experimental and control groups were both significantly higher than in the sham injury group. The immediate pre-injury administration of PP1 neither reduced cerebral oedema (water content %) nor preserved neurological function (NSS) when compared to a control group in this model of cortical cryoinjury.