Ischemic preconditioning is mediated by erythropoietin through PI-3 kinase signaling in an animal model of transient ischemic attack

Malhotra, Samit; Savitz, Sean I; Ocava, Lenore; Rosenbaum, Daniel M.

doi:10.1002/jnr.20705

Cited by 62 publications

(44 citation statements)

References 37 publications

(48 reference statements)

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“…This is consistent with our previous observations that NRG-1 protects neurons from delayed neuronal death and apoptosis in vivo [43][44][45]. The PI3K/Akt signaling pathway is a well described survival and anti-apoptotic factor in neurons and other cells during ischemia [18,21,23,26,46]. Binding of NRG-1 erbB receptors has been shown to activate the PI3K/Akt pathway [3,4,12].…”

Section: Discussionsupporting

confidence: 91%

Neuroprotective effects of neuregulin-1 on B35 neuronal cells following ischemia

et al. 2008

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We previously showed that neuregulin-1 (NRG-1) protected neurons from death in vivo following focal ischemia. The goal of this study was to develop an in vitro rat ischemia model to examine the cellular and molecular mechanisms involved in the neuroprotective effects of NRG-1 on ischemiainduced neuronal death. Rat B-35 neuroblastoma cells differentiated by serum withdrawal, developed enhanced neuronal characteristics including, neurite extension and upregulation of neuronal markers of differentiation. When B35 neurons were subjected to oxygen glucose deprivation (OGD)/ reoxygenation or glutamate, widespread neuronal death was seen after both treatments. Treatment with NRG-1 immediately after OGD significantly increased neuronal survival. NRG-1 administration also resulted in a significant decrease in annexin V, an early marker of apoptosis. However, the neurotoxic actions of glutamate were unaffected by NRG-1. The neuroprotective effects of NRG-1 were prevented by an inhibitor of the phosphatidylinositol-3-kinase/Akt pathway. These results provide a new model to gain insight into the mechanisms employed by NRG-1 to protect neurons from ischemic brain injury.

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Section: Discussionsupporting

confidence: 91%

Neuroprotective effects of neuregulin-1 on B35 neuronal cells following ischemia

et al. 2008

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“…The involvement of Akt in EPO-induced preconditioning has been reported in rat cortical neuronal cultures and in models of ischaemic preconditioning and acute neuroprotection in vivo. 11,16,17,31,32 Similarly, the activation of Stat5 by EPO has provided indirect evidence for a contribution of Stat5 in EPO neuroprotection both in animal models of cerebral ischaemia and in neuronal cultures exposed to oxidative stress. 6,[8][9][10] In a recent study, the EPO-induced Stat5 activity and neuroprotection was blocked by the JAK2 inhibitor, AG490.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to Stat5, best characterized from these are the phosphatidylinositol-3 0 kinase (PI3K)/ Akt, nuclear factor-kB and Ras/mitogen-activated protein kinase (Ras/MAPK) pathways. [6][7][8]10,[12][13][14][15][16][17] To directly test whether activation of Stat5 in neurons is essential for EPO actions, we examined the neuroprotective and neurotrophic effects of EPO in hippocampal neuronal cultures isolated from Stat5 À/À and Stat5 þ / þ mouse fetuses, 2 after acute abrogation of JAK2/Stat phosphorylation by the newly available pathway-specific inhibitor, cucurbitacin I. 18,19 Since Stat5 has been shown to be crucial for intracellular signalling and the somatotrophic effects of GH, 20,21 we studied in parallel its effects in the Stat5 À/À and Stat5 þ / þ neurons.…”

mentioning

confidence: 99%

Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

et al. 2008

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The transcription factors signal transducer and activator of transcription 5a and 5b (Stat5) are activated by the neuroprotective and neurotrophic cytokines, erythropoietin (EPO) and growth hormone (GH). Here, we show a dissociation of the intracellular pathway mediating the protective effect of EPO against glutamate toxicity from that needed for its neurotrophic activity using hippocampal neuronal cultures from Stat5a/b-knockout (Stat5 À/À ) mouse fetuses. Both pretreatment and post-treatment with EPO counteracted glutamate-induced cell death in Stat5 þ / þ and Stat5 À/À neurons. Acute pharmacological inhibition of Janus kinase 2 (JAK2)/Stat signalling had no effect on EPO neuroprotection, whereas inhibition of phosphatidylinositol-3 0 kinase (PI3K)/Akt pathway abolished the protective effect of EPO in both Stat5 þ / þ and Stat5 À/À neurons. GH effectively protected Stat5 þ / þ cells against glutamate toxicity but had no effect in Stat5 À/À neurons or in Stat5 þ / þ neurons treated with JAK2/Stat or PI3K inhibitor. EPO and GH stimulated neurite outgrowth and branching of Stat5 þ / þ neurons by activating PI3K/Akt signalling but had no trophic effect in Stat5 À/À cells. We conclude that in hippocampal neurons, Stat5 is not required for neuroprotection by EPO but is together with Akt essential for its neurotrophic activity. Both Stat5 and Akt are needed for neuroprotective and neurotrophic signalling of GH in neurons. The transcription factors signal transducer and activator of transcription 5a and 5b (Stat5) control cell fate decisions such as differentiation, proliferation and apoptosis. 1 Stat5 mediates cellular response to cytokines, growth factors and hormones. 1 Upon binding to their membrane receptors, growth factors such as erythropoietin (EPO) and growth hormone (GH) activate Janus kinase 2 (JAK2), causing activation of Stat5 by its phosphorylation, dimerization and translocation to the nucleus, where Stat5 induces expression of various antiapoptotic genes. 1 Indicative of an impaired functioning of EPO and GH receptor-associated signalling, Stat5a/b-knockout mice (Stat5 À/À ) are severely anaemic and growth retarded and the vast majority die perinatally. 2 Stat5 is expressed in the developing nervous system. 3,4 Recent studies suggest a role for Stat5 in neuronal migration and axon guidance in the developing brain 3 and a novel therapeutic potential for constitutively active Stat5 in reducing axonal outgrowth defects in spinal muscular atrophy-like motor neurons. 5 Since activation of Stat5 in neurons accompanies the antiapoptotic and neuroprotective effects of EPO in vitro and in vivo, 6-12 Stat5 has been suggested to mediate the protective effects of EPO in neuronal cells. Nevertheless, the molecular mechanisms of EPO receptor (EPOR) activation in neurons are complex, as multiple neuroprotective signalling pathways are activated downstream of EPOR/JAK2. In addition to Stat5, best characterized from these are the phosphatidylinositol-3 0 kinase (PI3K)/ Akt, nuclear factor-kB and Ras/mitogen-activated p...

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“…In various mouse and rat models of ischemia, intracerebral injection of Epo also attenuated brain damage by reducing infarct volume by up to 50% (6, 106, 107) and improved cognitive function (108)(109)(110). This was further underlined by the fact that cerebral administration of soluble EpoR reduced the protective effect of hypoxia preconditioning by up to 80% in other models (111,112). Overall exogenous Epo administration (see Fig.…”

Section: Neuroprotection By Epo In Vitromentioning

confidence: 92%

Epo and Non-hematopoietic Cells: What Do We Know?

Ogunshola

Bogdanova

2013

Methods in Molecular Biology

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Ischemic preconditioning is mediated by erythropoietin through PI-3 kinase signaling in an animal model of transient ischemic attack

Cited by 62 publications

References 37 publications

Neuroprotective effects of neuregulin-1 on B35 neuronal cells following ischemia

Neuroprotective effects of neuregulin-1 on B35 neuronal cells following ischemia

Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

Epo and Non-hematopoietic Cells: What Do We Know?

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