Neuroprotective profile of novel SRC kinase inhibitors in rodent models of cerebral ischemia.
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.
Liang
Shi
S
Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA.
Pong
Kevin
K
Gonzales
Cathleen
C
Chen
Yi
Y
Ling
Huai-Ping
HP
Mark
Robert J
RJ
Boschelli
Frank
F
Boschelli
Diane H
DH
Ye
Fei
F
Barrios Sosa
Ana Carolina
AC
Mansour
Tarek S
TS
Frost
Philip
P
Wood
Andrew
A
Pangalos
Menelas N
MN
Zaleska
Margaret M
MM
D000814:Aniline Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology; D002199:Capillary Permeability; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D005434:Flow Cytometry; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D009570:Nitriles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C545736:4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(4-(4-methypiperazin-1-yl)but-1-ynyl)-3-quinolinecarbonitrile; D000814:Aniline Compounds; D018696:Neuroprotective Agents; D009570:Nitriles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; D019061:src-Family Kinases