Src Family Kinase Inhibitor PP1 Reduces Secondary Damage after Spinal Cord Compression in Rats

Abstract

The synthetic pyrazolopyrimidine, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) is a novel, potent, and selective inhibitor of Src family tyrosine kinases. Vascular permeability appears to be mediated by vascular endothelial growth factor (VEGF), which requires the activation of downstream Src family kinases to exert its function. This study investigates the effects of PP1 on vascular permeability and inflammatory response in a rat spinal cord compression model. Ten minutes after compression, PP1 (PP1 group) or the vehicle only (control group) was administered. On days 1, 3, and 7 after compression, the spinal cords were removed and examined histopathologically to determine the expression of VEGF and the extent of edema and inflammation. The dryweight method was used to measure the water content of the spinal cords. The mRNA levels of tumor necrosis factor a (TNFalpha) and interleukin 1beta (IL-1beta), which is related to inflammatory responses, were measured with a real-time polymerase chain reaction (RT-PCR) system 6 h after compression. Although VEGF expression was similar in both groups, the extent of contusional lesion in the PP1 group was reduced by approximately 35% on day 3. Moreover, the water content on days 1, 3, and 7 was significantly reduced and macrophage infiltration on days 3 and 7 was dramatically reduced in the PP1 group. TNF and IL-1beta mRNA expression in the PP1 group were also significantly reduced. These results indicate that PP1 reduces secondary damage after spinal cord injury.

Src Tyrosine Kinases Mediate Activations of NF-κB and Integrin Signal during Lipopolysaccharide-Induced Acute Lung Injury

“…In addition to lung, PP2 treatment 30 min after middle cerebral artery occlusion also reduced the infarct size of focal ischemic brain injuries (40). Moreover, the results of Akiyama et al (41) indicate that PP1 treatment 10 min after compression reduces secondary damage after spinal cord injury by significantly reducing contusion-induced lesion sizes, macrophage infiltration and the expressions of TNF-␣ and IL-1␤ mRNA. Moreover, following myocardial infarction, genetic or pharmacological blockade (with PP1) of Src TKs preserved endothelial cell barrier function and suppressed vascular permeability and infarct volume at 24 h, and improved long-term cardiac function, fibrosis, and survival (27).…”

Src family kinases regulate p38 MAPK-mediated IL-6 production in Kupffer cells following hypoxia

“…To test this hypothesis, a group of animals was treated with Src inhibitor PP1 and the effect of this treatment on Kupffer cell MAPK activation as well as the production of IL-6 and MCP-1 was determined following hypoxia. In this regard, PP1 has been shown to inhibit Src family kinases in previous studies (2,23,26). Our findings from these experiments suggest that Src family kinases also likely regulate p38-mediated IL-6 production following hypoxia.…”

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

“…The dosages were adjusted in an attempt to form a dose-response curve. PP1 is synthetic pyrazolopyrimidine, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo [3,4-d] pyrimidine (PP1) and is a novel, potent, and selective inhibitor of Src family tyrosine kinases (SFK) whereas PP3 is an inactive analogue of PP1 (Akiyama et al, 2004;Zhou and Menko, 2002).…”