Src kinase inhibition decreases thrombin-induced injury and cell cycle re-entry in striatal neurons.
Since Src kinase inhibitors decrease brain injury produced by intracerebral hemorrhage (ICH) and thrombin is activated following ICH, this study determined whether Src kinase inhibitors decrease thrombin-induced brain injury. Thrombin injections into adult rat striatum produced focal infarction and motor deficits. The Src kinase inhibitor PP2 decreased thrombin-induced Src activation, infarction in striatum and motor deficits in vivo. Thrombin applied to cultured post-mitotic striatal neurons caused: injury to axons and dendrites; many TUNEL positive neuronal nuclei; and re-entry into the cell cycle as manifested by cyclin D1 expression, induction of several other cell cycle genes and cyclin-dependent kinase 4 activation. PP2 dose-dependently attenuated thrombin-induced injury to the cultured neurons; and attenuated thrombin-induced neuronal cell cycle re-entry. These results are consistent with the hypotheses that Src kinase inhibitors decrease injury produced by ICH by decreasing thrombin activation of Src kinases and, at least in part, by decreasing Src induced cell cycle re-entry.
Liu
Da-Zhi
DZ
Department of Neurology, MIND Institute, Neuroscience and Genetics Graduate Programs, University of California at Davis, Sacramento, California 95817, USA. dzliu@ucdavis.edu
Cheng
Xi-Yuan
XY
Ander
Bradley P
BP
Xu
Huichun
H
Davis
Ryan R
RR
Gregg
Jeffrey P
JP
Sharp
Frank R
FR
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000633:toxicity*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D019061:src-Family Kinases; D013917:Thrombin