su-6656 and Brain-Ischemia

The present study has been undertaken to investigate the possible role of Src Kinases in a neuroprotective mechanism of ischemic postconditioning in mice. Bilateral carotid artery occlusion for 12 min followed by reperfusion for 24 h produced a significant increase in cerebral infarct size and neurological severity score along with impairment of memory and motor coordination. Ischemic postconditioning involving three episodes of 10 s carotid artery occlusion with intermittent reperfusion of 10 s proceeding ischemic insult of 12 min, produced a significant decrease in cerebral infarct size and neurological severity score along with reversal of ischemia-reperfusion induced impairment of memory and motor coordination. Ischemic postconditioning induced neuroprotective effects were significantly attenuated by pre-treatment of selective Src Kinase inhibitors SU-6656 (4 mg/kg i.p.) and PP1 (0.2 mg/kg i.p.). It may be concluded that the neuroprotective effect of ischemic postconditioning probably involves activation of Src Kinase pathway.

Topics: Animals; Brain Ischemia; Cerebral Infarction; Disease Models, Animal; Dose-Response Relationship, Drug; Indoles; Ischemic Postconditioning; Male; Maze Learning; Memory Disorders; Mice; Motor Activity; Muscle Strength; Neuroprotective Agents; Pyrazoles; Pyrimidines; Rotarod Performance Test; Severity of Illness Index; src-Family Kinases; Sulfonamides; Time Factors

Neurogenesis in the adult mammalian hippocampus may contribute to repairing the brain after injury. However, Molecular mechanisms that regulate neuronal cell proliferation in the dentate gyrus (DG) following ischemic stroke insult are poorly understood. This study was designed to investigate the potential regulatory capacity of non-receptor tyrosine kinase Src on ischemia-stimulated cell proliferation in the adult DG and its underlying mechanism.. Src kinase activated continuously in the DG 24 h and 72 h after transient global ischemia, while SU6656, the Src kinase inhibitor significantly decreased the number of bromodeoxyuridine (BrdU) labeling-positive cells of rats 7 days after cerebral ischemia in the DG, as well as down-regulated Raf phosphorylation at Tyr(340/341) site, and its down-stream signaling molecules ERK and CREB expression followed by 24 h and 72 h of reperfusion, suggesting a role of Src kinase as an enhancer on neuronal cell proliferation in the DG via modifying the Raf/ERK/CREB cascade. This hypothesis is supported by further findings that U0126, the ERK inhibitor, induced a reduction of adult hippocampal progenitor cells in DG after cerebral ischemia and down-regulated phospho-ERK and phospho-CREB expression, but no effect was detected on the activities of Src and Raf.. Src kinase increase numbers of newborn neuronal cells in the DG via the activation of Raf/ERK/CREB signaling cascade after cerebral ischemia.

Topics: Analysis of Variance; Animals; Blotting, Western; Brain Ischemia; Butadienes; Cell Count; Cell Proliferation; Cyclic AMP Response Element-Binding Protein; Dentate Gyrus; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Immunohistochemistry; Indoles; Male; Neurons; Nitriles; Phosphorylation; raf Kinases; Rats; Rats, Sprague-Dawley; Reperfusion; Signal Transduction; src-Family Kinases; Sulfonamides