PT  - JOURNAL ARTICLE
AU  - Shi Liang
AU  - Kevin Pong
AU  - Cathleen Gonzales
AU  - Yi Chen
AU  - Huai-Ping Ling
AU  - Robert J. Mark
AU  - Frank Boschelli
AU  - Diane H. Boschelli
AU  - Fei Ye
AU  - Ana Carolina Barrios Sosa
AU  - Tarek S. Mansour
AU  - Philip Frost
AU  - Andrew Wood
AU  - Menelas N. Pangalos
AU  - Margaret M. Zaleska
TI  - Neuroprotective Profile of Novel Src Kinase Inhibitors in Rodent Models of Cerebral Ischemia
AID  - 10.1124/jpet.109.156562
DP  - 2009 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 827--835
VI  - 331
IP  - 3
4099  - http://jpet.aspetjournals.org/content/331/3/827.short
4100  - http://jpet.aspetjournals.org/content/331/3/827.full
SO  - J Pharmacol Exp Ther2009 Dec 01; 331
AB  - Src kinase signaling has been implicated in multiple mechanisms of ischemic injury, including vascular endothelial growth factor (VEGF)-mediated vascular permeability that leads to vasogenic edema, a major clinical complication in stroke and brain trauma. Here we report the effects of two novel Src kinase inhibitors, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile (SKI-606) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-(4-methypiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927), on ischemia-induced brain infarction and short- and long-term neurological deficits. Two well established transient [transient middle cerebral artery occlusion (tMCAO)] and permanent [permanent middle cerebral artery occlusion (pMCAO)] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario. Brain penetration of Src inhibitors, their effect on blood-brain barrier integrity and VEGF signaling in human endothelial cells were also evaluated. Our results demonstrate that both agents potently block VEGF-mediated signaling in human endothelial cells, penetrate rat brain upon systemic administration, and inhibit postischemic Src activation and vascular leakage. Treatment with SKI-606 or SKS-927 (at the doses of 3–30 mg/kg i.v.) resulted in a dose-dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4- to 6-h after tMCAO. Src blockade after pMCAO resulted in accelerated improvement in recovery from motor, sensory, and reflex deficits during a long-term (3 weeks) testing period poststroke. These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke.© 2009 by The American Society for Pharmacology and Experimental Therapeutics