Erythropoietin Increases Glutathione Peroxidase Enzyme Activity and Decreases Lipid Peroxidation Levels in Hypoxic-Ischemic Brain Injury in Neonatal Rats

Kumral, Abdullah; Gönenç, Sevil; Açıkgöz, Osman; Sönmez, Ataç; Genç, Kürşad; Yılmaz, Osman; Gökmen, Necati; Duman, Nuray; Özkan, Hasan

doi:10.1159/000080490

Cited by 111 publications

(86 citation statements)

References 24 publications

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“…Activation of the Janus kinase/Stat5 pathway, along with nuclear factor kappa B (NFkB) and Akt phosphorylation, appears to be responsible for reduced apoptotic cell death after Epo. 38,39 Other acute neuroprotective mechanisms include antiinflammatory, 40,41 antiexcitotoxic, 42 and antioxidant 43 effects. Epo also stimulates growth factors 44,45 and enhances neurogenesis, angiogenesis, and long-term repair and plasticity, thus providing neuroprotective and trophic effects that last well beyond the acute period of injury.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

et al. 2012

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“…Consistent with this finding, rhEPO treatment in rats with cisplatin-induced (12,13) or ischemia-and reperfusion-induced (14) acute renal failure enhances their functional recovery. Moreover, in contrast to the concerns about the rhEPO treatment-associated potential deterioration of renal function (15), clinical studies have reported that rhEPO could retard disease progression to chronic renal failure (16 -18) by anemia correction (19), proangiogenic properties (20 -22), reduction of oxidative stress (23), and antiapoptotic effects (24 -26). However, it is unknown whether the beneficial effects of rhEPO in chronic renal diseases are related to the inhibition of EMT.…”

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confidence: 99%

Erythropoietin Decreases Renal Fibrosis in Mice with Ureteral Obstruction

Park¹,

Choi²,

Song³

et al. 2007

Journal of the American Society of Nephrology

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The inhibitory effects of recombinant human erythropoietin (rhEPO) were examined against (1) the progression of renal fibrosis in mice with complete unilateral ureteral obstruction and (2) the TGF-␤1-induced epithelial-to-mesenchymal transition (EMT) in MDCK cells. Unilateral ureteral obstruction was induced in BALB/c mice and rhEPO (100 or 1000 U/kg, intraperitoneally, every other day) or vehicle was administered from day 3 to day 14. Immunoblotting and immunohistochemistry revealed increased expressions of TGF-␤1, ␣-smooth muscle actin (␣-SMA), and fibronectin and decreased expression of E-cadherin in the obstructed kidneys. In contrast, rhEPO treatment significantly attenuated the upregulation of TGF-␤1 and ␣-SMA and the downregulation of E-cadherin. MDCK cells were treated with TGF-␤1 (5 ng/ml) for 48 h to induce EMT, and the cells were then co-treated with TGF-␤1 and rhEPO for another 48 h. Increased expressions of ␣-SMA and vimentin and decreased expressions of zona occludens-1 and E-cadherin were observed after TGF-␤1 treatment, and these changes were markedly attenuated by rhEPO co-treatment. TGF-␤1 increased phosphorylated Smad-2 expression in MDCK cells, which was decreased by rhEPO co-treatment. In conclusion, rhEPO treatment inhibits the progression of renal fibrosis in obstructed kidney and attenuates the TGF-␤1-induced EMT. It is suggested that the renoprotective effects of rhEPO could be mediated, at least partly, by inhibition of TGF-␤1-induced EMT.

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“…Ehrenreich [32] have demonstrated that EPO achieves its protective effects via its antioxidant, anti-apoptotic effects rather than by regulating disease-specific pathological mechanisms. Similarly, Kumral et al [33] have reported that EPO increases GPx activity and decreases lipid peroxidation in neonatal rats exposed to hypoxia compared with controls. Kuzugüden et al [34] have shown the oxidative stress induced by high doses of thinner can be reduced by EPO via a decrease in the formation of MDA and an increase in GPx activity in rat brain.…”

Section: Discussionmentioning

confidence: 79%

The effects of erythropoietin and dextran and saline on brain edema and lipid peroxidation in experimental head trauma.

Başarslan

Göçmez

Kamaşak

et al. 2015

Ulus Travma Acil Cerrahi Derg

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Erythropoietin Increases Glutathione Peroxidase Enzyme Activity and Decreases Lipid Peroxidation Levels in Hypoxic-Ischemic Brain Injury in Neonatal Rats

Cited by 111 publications

References 24 publications

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

Erythropoietin Decreases Renal Fibrosis in Mice with Ureteral Obstruction

The effects of erythropoietin and dextran and saline on brain edema and lipid peroxidation in experimental head trauma.

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