Src family kinase inhibitor PP1 reduces secondary damage after spinal cord compression in rats.
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.
Department of Neurosurgery, Osaka University Medical School, Suita, Japan.
Chihiro
C
Akiyama
Takamichi
T
Yuguchi
Masami
M
Nishio
Takahiro
T
Tomishima
Toshiyuki
T
Fujinaka
Masaaki
M
Taniguchi
Yoshikazu
Y
Nakajima
Eiji
E
Kohmura
Toshiki
T
Yoshimine
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D004487:Edema / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D007375:Interleukin-1 / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013117:Spinal Cord Compression / Q000188:drug therapy* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000187:drug effects; D019061:src-Family Kinases / Q000187:drug effects*
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases