Sustained activation of Src-family tyrosine kinases by ischemia: A potential mechanism mediating extracellular signal-regulated kinase cascades in hippocampal dentate gyrus

Guo, J.; Wu, Hui‐Wen; Hu, Gang; Han, Xiao; De, Wei; Sun, Yingxin

doi:10.1016/j.neuroscience.2006.08.031

Cited by 32 publications

(55 citation statements)

References 34 publications

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“…Results from our studies show directly for the first time that focal ischemia with reperfusion induces activation of Src kinase in the area of the ischemic core for at least 6 h poststroke, with some up-regulation of activated Src in surrounding cortical areas. These data add to previous reports demonstrating an up-regulation of Src activity in a global ischemia model that mimics cardiac arrest rather than ischemic stroke (Zalewska et al, 2005;Guo et al, 2006). Our results show that the focal ischemia-induced up-regulation of Src is significantly reduced throughout this 6-h period after a single intravenous bolus of SKS-927.…”

Section: Discussionsupporting

confidence: 87%

“…Five members of the Src family PTKs (Src, Fyn, Yes, Lck, and Lyn) are highly expressed in platelets and in the mammalian CNS. Src family kinases have been shown to be activated after global ischemia and to potentiate the activity of NMDA receptors (Salter and Kalia, 2004;Guo et al, 2006) and voltage-gated calcium and potassium channels (Cataldi et al, 1996;Fadool et al, 1997), all known contributors to ischemic cell death.…”

mentioning

confidence: 99%

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Neuroprotective Profile of Novel Src Kinase Inhibitors in Rodent Models of Cerebral Ischemia

Shi

Pong²,

Gonzales³

et al. 2009

J Pharmacol Exp Ther

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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 longterm 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.Ischemic stroke is a life-threatening disorder, with no effective therapy except for intravascular thrombolysis with recombinant tissue plasminogen activator or, in some instances, surgical removal of the obstructing blood clot with interventional devices (Donnan et al., 2008;Zaleska et al., 2009). However, the risk of hemorrhage and a restrictive 3-to 4.5-h treatment window (Hacke et al., 2008) reduce the pool of patients eligible for treatment with recombinant tissue plasminogen activator to only 5 to 8%. Despite continued improvement in our understanding of mechanisms underlying ischemic damage and the identification of numerous neuroprotective agents effective in animal models, no agent has yet demonstrated significant benefit in the clinic (O'Collins et al., 2006;Savitz and Fisher, 2007;Zaleska et al., 2009). Hence, the development of stroke therapeutic agents remains a daunting challenge as does the urgent need for new agents.The Src family of nonreceptor protein tyrosine kinases (PTKs) coordinate a broad spectrum of physiological responses including extracellular signals derived from growth facto...

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Section: Discussionsupporting

confidence: 87%

mentioning

confidence: 99%

Neuroprotective Profile of Novel Src Kinase Inhibitors in Rodent Models of Cerebral Ischemia

Shi

Pong²,

Gonzales³

et al. 2009

J Pharmacol Exp Ther

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“…The downstream activation of Src by MAPK and cross-talk between these pathways has been shown elsewhere. 34,35 There were no changes in total Akt, MAPK, or Src levels at 4 h after trophic factor delivery ( Figure 7), indicating that the increased levels of phosphorylated Akt, MAPK, and Src were due to activation of existing intracellular pools. These findings show that at the concentrations used in our in vivo studies, LY294002, PD98059, and PP2 were selective for their specific intracellular kinases as described previously.…”

Section: Resultsmentioning

confidence: 98%

The upregulation of GLAST-1 is an indirect antiapoptotic mechanism of GDNF and neurturin in the adult CNS

Koeberle

Bähr

2007

Cell Death Differ

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Glial cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) protect retinal ganglion cells (RGCs) from axotomyinduced apoptosis. It is likely that neuroprotection by GDNF or NTN in the adult central nervous system (CNS) involves indirect mechanisms and independent signal transduction events. Extracellular glutamate is a trigger of apoptosis in injured RGCs, and glutamate transporter levels can be upregulated by GDNF. Therefore, GDNF may indirectly protect RGCs by enhancing glutamate uptake in the retina. We studied the upregulation of the glutamate transporters GLAST-1 and GLT-1 by GDNF and NTN, and the intracellular pathways required for GDNF/NTN neuroprotection. GDNF required phosphoinositide-3 kinase (PI3K) and Src activity to upregulate GLAST-1 and GLT-1. NTN required PI3K activity to upregulate GLAST-1 and did not affect GLT-1 levels. PI3K activity was also important for GDNF and NTN neuroprotection following optic nerve transection. However, GDNF also required Src and mitogen-activated protein kinase activity to prevent RGC apoptosis. RNA interference demonstrated that the upregulation of GLAST-1 by GDNF and NTN is required to rescue RGCs. Thus, additional independent signal transduction events, together with the upregulation of GLT-1 by GDNF, differentiate the biological activity of GDNF from NTN. Furthermore, the upregulation of the glial glutamate transporter GLAST-1 by both factors is an indirect neuroprotective mechanism in the CNS.

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“…Within several hours of reperfusion following global ischaemia, a general increase in the level of tyrosine phosphorylation at hippocampal Src was observed [135,136]; as well, a specific increase in Y416 phosphorylation was found within the whole hippocampus [38,79,248,258,273], and the CA1 [130,264,273] and CA3-dentate gyrus [79] regions. The level of phosphorylated Y416 was also found to be increased in both synaptosomes [160] and post-synaptic densities [16,35,160] prepared from the rodent forebrain region after the return of blood supply to the insulted area.…”

Section: Ischaemia and The General Cellular Pattern Of Tyrosine Phospmentioning

confidence: 86%

Tyrosine Phosphorylation of the NMDA Receptor Following Cerebral Ischaemia

Pavlov¹,

Mielke²

2012

Protein Phosphorylation in Human Health

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Sustained activation of Src-family tyrosine kinases by ischemia: A potential mechanism mediating extracellular signal-regulated kinase cascades in hippocampal dentate gyrus

Cited by 32 publications

References 34 publications

Neuroprotective Profile of Novel Src Kinase Inhibitors in Rodent Models of Cerebral Ischemia

Neuroprotective Profile of Novel Src Kinase Inhibitors in Rodent Models of Cerebral Ischemia

The upregulation of GLAST-1 is an indirect antiapoptotic mechanism of GDNF and neurturin in the adult CNS

Tyrosine Phosphorylation of the NMDA Receptor Following Cerebral Ischaemia

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