Erythropoietin after Focal Cerebral Ischemia Activates the Janus Kinase–Signal Transducer and Activator of Transcription Signaling Pathway and Improves Brain Injury in Postnatal Day 7 Rats

Sola, Augusto; Rogido, M.; Lee, Ben H.; Genetta, T.; Wen, Tong-Chun

doi:10.1203/01.pdr.0000155760.88664.06

Cited by 125 publications

(89 citation statements)

References 44 publications

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“…In contrast, another study showed that the level of p-STAT5 in cultured hippocampal neurons was maintained at a relatively higher level by EPO at 15 hr of hypoxia, but was lower than that in the normoxia condition (Siren et al, 2001). At 1 day and 3 days after focal cerebral ischemia in neonatal rats, the level of p-STAT5 was higher in EPO groups than that in ischemic groups, similar to the in vitro study discussed above (Sola et al, 2005). However, 15 hr after hypoxia in neuronal culture and day 1 and day 3 after focal cerebral ischemia in animal models represented the late stages of ischemic insult, at which time robust cell death have already occurred.…”

Section: Discussionsupporting

confidence: 62%

“…EPO is also demonstrated to be able to promote the phosphorylation and activation of STAT5 through JAK2 (Damen et al, 1995, Gobert et al, 1996, Parganas et al, 1998, Siren et al, 2001, Sola et al, 2005. Following cerebral ischemia, apoptosis is an important cell death mechanism, especially in the injury of hippocampal CA1 neurons induced by global ischemia (Zhang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia

Zhang

Wang

Cao

et al. 2007

Neurobiology of Disease

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The signal transducers and activators of transcription (STAT) proteins are a group of transcriptional factors. Among them, STAT5 initiates a pro-survival signaling cascade. So far, little has been known about the role of STAT5 in cerebral ischemia and reperfusion. This study examines the phosphorylation status of STAT5 in hippocampal CA1 in the early stage after transient global cerebral ischemia in rats. Our data show that the phosphorylation of STAT5 was increased in hippocampal CA1 at 1 hour and 3 hours ischemia. Taking advantage of the neuroprotective effect of erythropoietin (EPO) in CA1, we further demonstrated that the administration of EPO enhanced the phosphorylation of STAT5, with SATA5a being phosphorylated earlier. The enhanced phosphorylation of STAT5 in the EPO-treated group was accompanied by the upregulation of STAT5 downstream gene products, Bcl-xL and XIAP. Consequently, ischemic CA1 neuronal damage was attenuated by the administration of EPO. Both the enhancement of STAT5 phosphorylation and the neuroprotection rendered by EPO were blocked by Tyrphostin, a selective inhibitor for Janus kinase 2, which is an upstream kinase of STAT5. These findings suggest an association between the activation of STAT5 and CA1 neuronal survival after cerebral ischemia.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia

Zhang

Wang

Cao

et al. 2007

Neurobiology of Disease

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“…23,25 Multiple doses of Epo reduce infarct volume in a dose-dependent manner. 21 Epo reduces neuronal loss and learning impairment after HI brain injury. 17,20 When initiated as late as 48 to 72 hours after injury, there is evidence of improved behavioral outcomes, enhanced neurogenesis, increased axonal sprouting, and reduced white matter injury.…”

Section: Discussionmentioning

confidence: 98%

“…[12][13][14][15][16][17][18][19] High doses of Epo administered to neonatal rodents after hypoxic-ischemic (HI) brain injury results in improved histologic and functional outcomes including improved memory and swim speed. 17,[20][21][22][23][24][25][26][27] Two clinical trials suggest that infants with HIE treated with 5 to 7 doses of Epo experience improved neurologic outcomes. 28,29 However, small patient numbers, short length of follow-up, 29 and lack of intention-totreat analysis 28 limit conclusions from these studies.…”

mentioning

confidence: 99%

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

et al. 2012

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OBJECTIVE: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000–10 000 U/L; area under the curve = 117 000–140 000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.

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“…In an adult animal model of ischemic stroke, exogenous EPO reduces an infarct size (2,4,17,26,32). In the neonatal animal model, exogenous EPO improves asymmetry of forelimbs following stroke (18), reduces the infarct size with attenuation of brain injury, and preserves the integrity of cerebral cortex (33,34). EPO induces time-and dose-dependent tolerance against oxygen and glucose deprivation in primary cortical neurons and protects from cell death.…”

Section: Erythropoietin In Cardiopulmonary Resuscitation: Are We Near?mentioning

confidence: 99%

Erythropoietin in post-resuscitation neurological recovery: is there light at the end of the tunnel?

Kupnik

Grmec

2007

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Erythropoietin after Focal Cerebral Ischemia Activates the Janus Kinase–Signal Transducer and Activator of Transcription Signaling Pathway and Improves Brain Injury in Postnatal Day 7 Rats

Cited by 125 publications

References 44 publications

Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia

Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

Erythropoietin in post-resuscitation neurological recovery: is there light at the end of the tunnel?

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