Protective Effect Of Erythropoietin Research Articles

The Protective Effect of Erythropoietin in Kidney

促红细胞生成素(EPO)是一种多功能因子.肾是EPO分泌的主要器官,并有EPO受体表达.EPO与其受体结合后,通过抑制炎性反应,减少超氧损伤,减少细胞凋亡和坏死,促进再生,阻止肾的水通道和钠运载体下调,促进血管生成,减轻内皮损害、肾血管球硬化和小管间质性损伤而发挥肾保护作用.通过信号传导因子和转录激活因子、磷脂酰肌醇3激酶、核因子-κB、热休克蛋白等信号途径发挥其作用.目前对临床应用EPO的肾保护作用尚存争议。

Protective effects of erythropoietin against acute lung injury in a rat model of acute necrotizing pancreatitis

To investigate the effect of exogenous erythro-poietin (EPO) administration on acute lung injury (ALI) in an experimental model of sodium taurodeoxycholate- induced acute necrotizing pancreatitis (ANP). Forty-seven male Wistar albino rats were randomly divided into 7 groups: sham group (n = 5), 3 ANP groups (n = 7 each) and 3 EPO groups (n = 7 each). ANP was induced by retrograde infusion of 5% sodium taurodeoxycholate into the common bile duct. Rats in EPO groups received 1000 U/kg intramuscular EPO immediately after induction of ANP. Rats in ANP groups were given 1 mL normal saline instead. All animals were sacrificed at postoperative 24 h, 48 h and 72 h. Serum amilase, IL-2, IL-6 and lung tissue malondialdehyde (MDA) were measured. Pleural effusion volume and lung/body weight (LW/BW) ratios were calculated. Tissue levels of TNF-alpha, IL-2 and IL-6 were screened immunohistochemically. Additionally, ox-LDL accumulation was assessed with immune-fluorescent staining. Histopathological alterations in the lungs were also scored. The mean pleural effusion volume, calculated LW/BW ratio, serum IL-6 and lung tissue MDA levels were significantly lower in EPO groups than in ANP groups. No statistically significant difference was observed in either serum or tissue values of IL-2 among the groups. The level of tumor necrosis factor-alpha (TNF-alpha) and IL-6 and accumulation of ox-LDL were evident in the lung tissues of ANP groups when compared to EPO groups, particularly at 72 h. Histopathological evaluation confirmed the improvement in lung injury parameters after exogenous EPO administration, particularly at 48 h and 72 h. EPO administration leads to a significant decrease in ALI parameters by inhibiting polymorphonuclear leukocyte (PMNL) accumulation, decreasing the levels of proinflammatory cytokines in circulation, preserving microvascular endothelial cell integrity and reducing oxidative stress-associated lipid peroxidation and therefore, can be regarded as a cytoprotective agent in ANP-induced ALI.

Protective effects of erythropoietin against acute lung injury in a rat model of acute necrotizing pancreatitis

瞄准：为了调查外长的 erythro-poietin (EPO ) 的效果，在钠 taurodeoxycholate- 的一个试验性的模型的尖锐的肺损害(ALI ) 上的管理导致了尖锐引起坏死胰腺炎(ANP ) 。方法：47 只男 Wistar 白鼠随机被划分成 7 个组：假冒的组(n = 5 ) ， 3 个 ANP 组(n = 7 各个) 并且 3 个 EPO 组(n = 7 各个) 。ANP 被导致由后退进胆总管的 5% 钠 taurodeoxycholate 的注入。在 EPO 组的老鼠收到了 1000 U/kg 肌内的 EPO 立即在 ANP 的正式就职以后。在 ANP 组的老鼠相反被给 1 mL 生理盐水。所有动物被牺牲在手术后 24 h， 48 h 和 72 h。浆液 amilase， IL-2， IL-6 和肺织物 malondialdehyde (MDA ) 被测量。胸膜渗漏体积和肺 / 身体重量(LW/BW ) 比率是计算的。TNF-alpha， IL-2 和 IL-6 的织物层次组织化学地是屏蔽免疫。另外， ox-LDL 累积与免疫者荧光灯的染色被估计。在肺的组织病理学说的改变也被获得。结果：吝啬的胸膜渗漏体积，计算 LW/BW 比率，浆液 IL-6 和肺织物 MDA 层次比在 ANP 组在 EPO 组是显著地更低的。不，统计上，有效差量在这些组之中在浆液或 IL-2 的织物价值被观察。当时， ox-LDL 的肿瘤坏死 factor-alpha (TNF-alpha ) 和 IL-6 和累积的水平在 ANP 组的肺纸巾是明显的与 EPO 组相比，特别地在 72 h。组织病理学说的评估在外长的 EPO 管理以后在肺损害参数证实了改进，特别地在 48 h 和 72 h。结论：EPO 管理由禁止 polymorphonuclear (PMNL ) 在 ALI 参数导致重要减少累积，减少专业版的层次在每氧化的循环，保存微脉管的内皮房间正直和减少的氧化联系压力的类脂化合物的煽动性的 cytokines 并且因此，能在导致 ANP 的 ALI 被认为是一个 cytoprotective 代理人。

Beyond erythropoiesis: The anti-inflammatory effects of erythropoietin

See article by Li et al. [4] (pages 684–694) in this issue. Erythropoietin (EPO) is a 30.4-kDa glycoprotein essential for red blood cell production. In adults, EPO is produced primarily in the kidney via an oxygen-sensing mechanism and stimulates erythroid progenitors in the bone marrow to increase red blood cell mass. In addition to its role in erythropoiesis, EPO has been shown to protect against ischemic injury in several organs including the heart. In various animal models, administration of EPO reduces infarct size and improves cardiac function following myocardial ischemia and reperfusion (I/R). The protective effects have been observed regardless of whether EPO was administered before ischemia, at the onset of ischemia, or at reperfusion [1,2]. The protective effects of EPO are also seen in chronic models of myocardial infarction (MI). In this regard, treatment of EPO before or immediately after coronary artery ligation decreases cardiac remodeling and improves myocardial function. Interestingly, a single dose of EPO (3000 IU/kg, i.p.) immediately after induction of MI improved cardiac function measured 8 weeks later. The therapeutic relevance of EPO was further demonstrated by van der Meer et al., who showed that EPO treatment started 3 weeks after MI improved cardiac function in a rat model of heart failure [3]. Consistent with this finding, in a report in this issue of Cardiovascular Research , EPO was started 6 weeks after induction of MI when heart failure was fully established in mice. Four weeks of EPO treatment diminished left … * Tel.: +1 519 685 8300x55443; fax: +1 519 685 8341. Email address: qfeng{at}uwo.ca

Erythropoietin protects cardiomyocytes from apoptosis via up-regulation of endothelial nitric oxide synthase

Erythropoietin (EPO), a cytokine best known for its ability to increase red blood cell mass, has recently been shown to protect cardiomyocytes from apoptotic cell death. The objective of the present study was to investigate the role of endothelial nitric oxide synthase (eNOS) in the anti-apoptotic effects of EPO in cardiomyocytes. Neonatal mouse ventricular cardiomyocytes were isolated and cultured from wild-type and eNOS(-/-) mice. Treatment with EPO significantly reduced apoptosis induced by norepinephrine (NE) in the wild-type cardiomyocytes. The reduction of apoptosis was associated with significant increases in eNOS expression, phosphorylation and NO production. However, the anti-apoptotic effects of EPO were significantly decreased in wild-type cardiomyocytes treated with L-NAME, which inhibits nitric oxide synthase activity. The results were further confirmed using eNOS(-/-) cardiomyocytes. To investigate the in vivo significance of eNOS in mediating the anti-apoptotic effects of EPO, wild-type and eNOS(-/-) mice were subjected to myocardial ischemia and reperfusion. EPO decreased myocardial apoptosis and infarct size in wild-type mice. However, the protective effects of EPO were significantly diminished in eNOS(-/-) mice. EPO increases eNOS expression and NO production in cardiomyocytes. The anti-apoptotic effects of EPO in cardiomyocytes are mediated by eNOS-derived NO production.

Protective Effect of Erythropoietin and Its Carbamylated Derivative in Experimental Cisplatin Peripheral Neurotoxicity

Antineoplastic drugs, such as cisplatin (CDDP), are severely neurotoxic, causing disabling peripheral neuropathies with clinical signs known as chemotherapy-induced peripheral neurotoxicity. Cotreatment with neuroprotective agents and CDDP has been proposed for preventing or reversing the neuropathy. Erythropoietin given systemically has a wide range of neuroprotective actions in animal models of central and peripheral nervous system damage. However, the erythropoietic action is a potential cause of side effects if erythropoietin is used for neuroprotection. We have successfully identified derivatives of erythropoietin, including carbamylated erythropoietin, which do not raise the hematocrit but retain the neuroprotective action exerted by erythropoietin. We have developed previously an experimental chemotherapy-induced peripheral neurotoxicity that closely resembles CDDP neurotoxicity in humans. The present study compared the effects of erythropoietin and carbamylated erythropoietin (50 microg/kg/d thrice weekly) on CDDP (2 mg/kg/d i.p. twice weekly for 4 weeks) neurotoxicity in vivo. CDDP given to Wistar rats significantly lowered their growth rate (P < 0.05), with slower sensory nerve conduction velocity (P < 0.001) and reduced intraepidermal nerve fibers density (P < 0.001 versus controls). Coadministration of CDDP and erythropoietin or carbamylated erythropoietin partially but significantly prevented the sensory nerve conduction velocity reduction. Both molecules preserved intraepidermal nerve fiber density, thus confirming their neuroprotective effect at the pathologic level. The protective effects were not associated with any difference in platinum concentration in dorsal root ganglia, sciatic nerve, or kidney specimens. These results widen the spectrum of possible use of erythropoietin and carbamylated erythropoietin as neuroprotectant drugs, strongly supporting their effectiveness.

Preventive Effect of Erythropoietin on Cardiac Dysfunction in Doxorubicin-Induced Cardiomyopathy

Doxorubicin is a highly effective antineoplastic drug, but its clinical use is limited by its adverse side effects on the heart. We investigated possible protective effects of erythropoietin against doxorubicin-induced cardiomyopathy. Cardiomyopathy was induced in mice by a single intraperitoneal injection of doxorubicin (15 mg/kg). In some cases, human recombinant erythropoietin (5000 U/kg) was started simultaneously. Two weeks later, left ventricular dilatation and dysfunction were apparent in mice given doxorubicin but were significantly attenuated by erythropoietin treatment. Erythropoietin also protected hearts against doxorubicin-induced cardiomyocyte atrophy and degeneration, myocardial fibrosis, inflammatory cell infiltration, and downregulation of expression of GATA-4 and 3 sarcomeric proteins, myosin heavy chain, troponin I, and desmin. Cyclooxygenase-2 expression was upregulated in doxorubicin-treated hearts, and that, too, was attenuated by erythropoietin. No doxorubicin-induced apoptotic effects were seen, nor were any changes seen in the expression of tumor necrosis factor-alpha or transforming growth factor-beta1. Antiatrophic and GATA-4 restoring effects of erythropoietin were demonstrated in the in vitro experiments with cultured cardiomyocytes exposed to doxorubicin, which indicated the direct cardioprotective effects of erythropoietin beyond erythropoiesis. Cardiac erythropoietin receptor expression was downregulated in doxorubicin-induced cardiomyopathy but was restored by erythropoietin. Among the downstream mediators of erythropoietin receptor signaling, activation of extracellular signal-regulated kinase was reduced by doxorubicin but restored by erythropoietin. By contrast, erythropoietin was ineffective when administered after cardiac dysfunction was established in the chronic stage. The present study indicates a protective effect of erythropoietin against doxorubicin-induced cardiomyopathy.

Erythropoietin Protects Cardiomyocytes Not Only during Hypoxic Injury but Also Against Doxorubicin-Induced Apoptosis: A Novel Effect Mediated by Phosphatidylinositol 3-Kinase Pathway.

Erythropoietin (EPO) is a tissue-protective cytokine that exerts cytoprotective effects against various types of injury in non-hematopoietic tissues. Our previous work using Langendorff-perfused adult rat hearts demonstrated that EPO improves left ventricular function and reduces infarct size during ischemia-reperfusion injury. Recent studies of EPO variants that retain tissue-protective properties of EPO in non-hematopoietic tissues without stimulating erythropoiesis suggested fundamental differences between EPO-mediated cellular signaling in hematopoietic versus non-hematopoietic cells as well as novel clinical applications for recombinant EPO and its derivatives in disorders other than anemia. In this study, we characterized the activation of EPO-mediated intracellular signal transduction in primary cardiac myocytes and determined the specific pathways required for protection of cardiomyocytes against hypoxic injury. We also investigated the ability of EPO to protect against cell death induced by doxorubicin (DOX), a chemotherapeutic agent associated with well-established cardiotoxic effects. We hypothesized that protective effects of EPO during hypoxic or DOX-mediated cardiomyocyte injury may be inhibited by specific kinase inhibitors targeting pathways activated by EPO. Primary cardiac myocytes were isolated from neonatal rat ventricles (NRVM) establishing cultures containing >97% cardiac myocytes as determined by immunostaining of cells with anti-cardiac muscle sarcomeric actinin. We found that EPO induces the rapid phosphorylation of PI3K substrate Akt and p44/42 MAP kinases Erk 1/2 in a time-dependent fashion. Constitutive tyrosine phosphorylation of Jak2 was observed that did not increase following EPO treatment of cardiomyocytes. Pre-incubation of cells with PI3K inhibitor LY294002 or MEK inhibitor U0126 prior to EPO treatment inhibited the increased phosphorylation of Akt and Erk1/2, respectively. EPO treatment of NRVMs significantly reduced hypoxia-induced apoptosis by 44% assessed by immunoflurescence microscopy of cardiomyocytes double-labeled with TUNEL and DAPI to quantify apoptotic nuclei (P<0.001 by ANOVA; hypoxia-treated versus hypoxia+EPO, n=12 fields of ~4,000 cells in each group). The ability of EPO to protect against hypoxia-mediated apoptosis was also confirmed by a cell-death ELISA that quantifies mono- and oligo-nucleosomes associated with apoptosis. Treatment of cells with LY294002 or protein kinase C inhibitor chelerythrine abolished the anti-apoptotic effect of EPO during hypoxia, whereas treatment with U0126 or Jak2 inhibitor AG490 did not. We also found that EPO exerts a significant protective effect during DOX-induced cell death in a dose-dependent manner, reducing apoptosis by 36% in TUNEL assays (P<0.001 by ANOVA; DOX-treated versus DOX+Epo, n= 6 fields of ~2,000 cells in each group) and by 29% in ELISA assays (P<0.001 by ANOVA, DOX-treated versus DOX+Epo, n=14). Treatment of cells with LY294002 abrogated the anti-apoptotic effect of EPO in NVRMs treated with DOX. These findings demonstrate that 1)-EPO induces rapid phosphorylation of Akt and Erk1/2 but not Jak2 in primary cardiac myocytes in a time-dependent fashion; 2)-EPO protects cardiomyocytes against apoptosis induced by hypoxia or DOX; 3)-The protective effect of EPO during hypoxia-mediated injury of cardiomyocytes requires the PI3K and PKC pathways, but not MAP kinase or Jak2 pathways; 4) The protective effect of EPO during DOX treatment of cardiomyocytes requires the PI3K pathway.

Protective effects of erythropoietin against ethanol-induced apoptotic neurodegenaration and oxidative stress in the developing C57BL/6 mouse brain

The developing central nervous system is extremely sensitive to ethanol, with well-defined temporal periods of vulnerability. Recent studies have shown that administration of ethanol to infant rats during the synaptogenesis period triggers extensive apoptotic neurodegeneration throughout many regions of the developing brain. Furthermore, acute ethanol administration produces lipid peroxidation in the brain as an indicator of oxidative stress. In recent years, it has been shown that erythropoietin (EPO) has a critical role in the development, maintenance, protection, and repair of the nervous system. In the present study, we investigated the effect of EPO against ethanol-induced neurodegeneration and oxidative stress in the developing C57BL/6 mouse brain. Seven-day-old C57BL/6 mice were divided into three groups: control group, saline-treated group, EPO-treated group. Ethanol was administered to mice at a dosage of 2.5 g/kg for two times with a 2-h interval. Recombinant human EPO (rhEPO) was given 1000 U/kg. Twenty-four hours after the first dose of ethanol, all the animals were killed. Neuronal cell death, apoptosis, thiobarbituric acid substance (TBARS) levels, superoxide dismutase (SOD), and glutathione peroxidase (Gpx) enzymes activities were evaluated. Histopathological evaluation demonstrated that EPO significantly diminished apoptosis in the cerebellum, prefrontal cortex, and hippocampus and also spared hippocampal CA1, CA2, and CA3 neurons. Simultaneous administration of EPO along with ethanol attenuated the lipid peroxidation process and restored the levels of antioxidants. Regarding the wide use of erythropoietin in premature newborns, this agent may be potentially beneficial in treating ethanol-induced brain injury in the perinatal period.

Erythropoietin attenuates renal injury in experimental acute renal failure ischaemic/reperfusion model

Erythropoietin (EPO), originally identified for its critical role in promoting erythrocyte survival and differentiation, has been shown to exert multiple paracrine/autocrine functions. Protective effects of EPO have been demonstrated in various tissues and experimental models of ischaemia-induced injury. In the present study, we investigated the effect of EPO on an in vivo rat model of renal ischaemia/reperfusion (I/R) injury and the possible mechanisms implicated in the EPO-mediated anti-apoptotic action. Male Wistar rats, subjected to renal ischaemia for 45 min, were administered either saline or EPO (500 U/kg, i.p.) 20 min prior to I/R. A sham-operated group served as the control. At 48 h of reperfusion, the renal dysfunction and injury was assessed by measurement of serum biochemical markers (urea, creatinine) and histological grading. Apoptosis was assessed by the TUNEL method and morphological criteria. Expression of Bax and NF-kappaB (p65) was also evaluated. High levels of serum urea and creatinine were identified at 48 h after ischaemia. The EPO-treated group had significantly lower serum and creatinine levels. Semi-quantitative assessment of the histological lesions showed that rats subjected to I/R developed marked structural damage, whereas significantly less tubular damage was observed in the EPO-treated group. I/R caused an increase in TUNEL-positive cells that was accompanied by morphological evidence of apoptosis. In the EPO-treated rats only a few scattered TUNEL-positive cells were observed. Up-regulation of Bax in the tubular epithelial cells and increased expression of NF-kappaB was observed in the I/R-treated rats, while diminished expression of Bax and positive immunostaining of NF-kappaB was observed in the EPO-treated rats. Administration of EPO as a single dose before the onset of ischaemia produced a significant reduction in tubular injury, which was accompanied by a marked amelioration of renal functional impairment. The cytoprotective action of EPO against I/R injury seems to be associated with its anti-apoptotic action. Moreover, transcription factor NF-kappaB is likely to play a pivotal role in the pathophysiology of I/R renal injury and might have a key role in EPO-mediated protective effects.

Erythropoietin protects the infant heart against ischemia?reperfusion injury by triggering multiple signaling pathways

The immediate protective effect of erythropoietin (EPO) against ischemia in heart suggests a role beyond hematopoiesis and the treatment of anemia. We determined the role of JAK/STAT and Ras/Rac/MAPK in the protective effect of EPO against ischemia-reperfusion injury in infant rabbit heart. EPO (1.0 U/ml) administered 15 minutes prior to 30-minutes global ischemia and 35 minutes reperfusion resulted in increased recovery of postischemic ventricular developed pressure in rabbit hearts. EPO exerted its immediate cardioprotective effect via activation of multiple signaling pathways by: 1) phosphorylation and activation of JAK1/2, STAT3 and STAT5A but not of STAT1alpha and STAT5B, 2) phosphorylation and activation of PI(3) kinase and its downstream kinases Akt and Rac, 3) activation of PKCepsilon, Raf, MEK1/2, p42/44 MAPK and p38 MAPK. Pretreatment with Wortmannin abolished EPO-induced Akt activation and phosphorylation. Pretreatment with Chelerythrine followed by EPO treatment resulted in partial inhibition of Raf activation, and abolished PKCepsilon and p38 MAPK activation without any effect on Akt, MEK1/2 and p42/44 MAPK. PD98059 abolished MEK1/2 and p42/44 MAPK activation with no effect on Akt, Raf and p38 MAPK activation. SB203580 inhibited only p38 MAPK activation by EPO. We can conclude EPO increases immediate cardioprotection through the activation of multiple signal transduction pathways.

Ultrastructural changes in tracheobronchial epithelia following experimental traumatic brain injury in rats: Protective effect of erythropoietin

Background We aimed to demonstrate the time dependent ultrastructural changes in tracheobronchial epithelia after traumatic brain injury. And also, protective effect of erythropoietin was demonstrated. Methods We used 56 Wistar-Albino female rats weighing 170 to 200 g. The rats were allocated into 7 groups. First group was the control. The second underwent craniotomy without trauma. The third, fourth, and fifth groups were respectively 2-, 8-, and 24-hour trauma groups. The sixth and seventh groups were respectively treatment (erythropoietin, 1,000 IU/kg) and vehicle (0,4 ml/rat) groups. Weight-drop method was used for achieving head trauma. Samples were obtained from both trachea and main bronchi. Modified electron microscopic scoring model was used to reveal the ultrastructural changes in both trauma and treatment groups. Results There was no statistical difference between control and sham groups ( p > 0.05). Scores of all trauma groups were significantly different from the controls ( p < 0.05). Trauma produced obvious gradual damage on ultrastructure of the tracheobronchial epithelia. Erythropoietin decreased tracheobronchial scores after traumatic brain injury in significant levels. Erythropoietin attenuated ultrastructural scores for each organelle in significant levels ( p < 0.05 for each organelle). Conclusions The data suggested that ultrastructural damage is obvious at 2 hours deteriorating with time. Erythropoietin protects epithelia against damage after traumatic brain injury. Pharmaceutical lung preservation may help gaining efficacious donor lungs in brain death. But, further time dependent experiments are needed to determine the liability of the donor lung after traumatic brain injury. This fact is to be known for achieving higher graft survival rates.

Mechanisms of Erythropoietin-Mediated Cardioprotection during Ischemia-Reperfusion Injury: Role of Protein Kinase C Signaling.

The biologic effects of erythropoietin (EPO) are mediated by its cellular receptor EPOR, a member of the cytokine receptor superfamily. EPOR expression in non-hematopoietic cells is associated with novel biologic effects for EPO in diverse organ systems. We recently demonstrated functional EPOR expression in adult rat cardiac myocytes and found that recombinant EPO exerts a rapid cardioprotective effect during ischemia-reperfusion injury of the isolated, perfused heart. Here we investigated the mechanisms of the cardioprotective effect of EPO using Langendorff-perfused rat hearts while left-ventricular-developed pressure (LVDP) was measured continuously to assess contractile function. Hearts were treated directly with EPO in the presence or absence of inhibitors of specific signal transduction pathways prior to normothermic global ischemia followed by reperfusion. Post-ischemic recovery of contractile function was determined by measuring LVDP at the end of reperfusion and expressed as a percentage of the baseline pre-treatment measurement. We investigated EPO-mediated activation of signal transduction pathways in the isolated, perfused heart and observed phosphorylation of p44/p42 MAP kinases ERK 1/2 (Thr202/Tyr204) and protein kinase B/Akt (Ser473), a downstream target of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Furthermore, EPO treatment of the isolated, perfused heart was associated with translocation of protein kinase C (PKC) ε and δ isoforms to the membrane fraction. We investigated the role of specific signaling pathways in EPO-mediated cardioprotection by employing inhibitors targeting PI3K, PKC and MAP kinase kinase (MEK1). PI3K inhibitors LY294002 and wortmannin attenuated EPO-induced phosphorylation of Akt but had no effect on EPO-mediated cardioprotection. MEK1 inhibitor U0126 had no effect on EPO-mediated cardioprotection. The PKC catalytic inhibitor chelerythrine (chel) significantly inhibited EPO-mediated improvement in post-ischemic recovery of LVDP (figure 1). Hearts pre-treated with EPO exhibited significantly improved post-ischemic recovery of LVDP compared to control hearts (mean±SE: 72±3 in EPO-treated versus 35±3% in control hearts, P<0.05 by ANOVA and Bonferroni post-hoc test, n=10 experiments each group) and the protective effect of EPO was significantly inhibited in chel-treated hearts (52±4% in EPO+chel versus 72±3% in EPO-treated hearts, P<0.05, n=10). As a control, treatment of the hearts with chelerythrine alone had no significant effect on LVDP (49±4%) compared to control hearts. These data demonstrate that EPO-mediated activation of the PKC signaling pathway is required for the cardioprotective effect of EPO during ischemia-reperfusion injury. [Display omitted]

Protective effect of erythropoietin in a neonatal model of brain damage

Protective effect of erythropoietin in a neonatal model of brain damage

A novel protective effect of erythropoietin in the infarcted heart.

Erythropoietin (EPO) has been shown to protect neurons from ischemic stroke, but can also increase thrombotic events and mortality rates in patients with ischemic heart disease. We reasoned that benefits of EPO might be offset by increases in hematocrit and evaluated the direct effects of EPO in the ischemic heart. We show that preconditioning with EPO protects H9c2 myoblasts in vitro and cardiomyocytes in vivo against ischemic injury. EPO treatment leads to significantly improved cardiac function following myocardial infarction. This protection is associated with mitigation of myocyte apoptosis, translating into more viable myocardium and less ventricular dysfunction. EPO-mediated myocyte survival appears to involve Akt activation. Importantly, cardioprotective effects of EPO were seen without an increase in hematocrit (eliminating oxygen delivery as an etiologic factor in myocyte survival and function), demonstrating that EPO can directly protect the ischemic and infarcted heart.

A novel protective effect of erythropoietin in the infarcted heart

A novel protective effect of erythropoietin in the infarcted heart

Protective effect of erythropoietin on the oxidative damage of erythrocyte membrane by hydroxyl radical

Treatment of red blood cells with the copper (II) ascorbate system causes increased lipid peroxidation, increased membrane microviscosity, and phospholipid translocation with a concurrent decrease in cytosolic catalase and glutathione peroxidase activities. All these changes are prevented if the cells are treated with erythropoietin prior to the exposure to copper (II) ascorbate. The present investigation further indicates that the oxidative damage brought about by copper (II) ascorbate is due to generation of hydroxyl radical and that erythropoietin plays a unique role in protecting the membrane from oxidative damage.

Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death

Recently, erythropoietin has been shown to be produced by astrocytes and its production is hypoxia-inducible. In the present study, we demonstrated, using a reverse transcription–polymerase chain reaction assay and immunostaining of the cells, that the erythropoietin receptor was expressed in cultured hippocampal and cerebral cortical neurons of day 19 rat embryo. Erythropoietin protected the cultured neurons from glutamate neurotoxicity. Neurons cultured for seven to 10 days were exposed to glutamate for 15 min and after culture for a further 24 h in the absence of glutamate the neuron survival was assayed. Significant protection was observed with erythropoietin from 3 pM ( c. 100 pg/ml) in a dose-dependent manner. The protection was completely reversed by co-application of a soluble erythropoietin receptor, an extracellular domain capable of binding with erythropoietin. For exhibition of the neuroprotective effect, exposure of neurons to erythropoietin approximately 8 h prior to exposure to glutamate was required. Experiments with the inhibitors indicated that RNA and protein syntheses were necessary for the protection. However, exposure to erythropoietin for a short period (5 min or less) was sufficient to elicit the protective effect. The protective effect of erythropoietin was blocked by the simultaneous addition of EGTA. These findings and the previous finding that erythropoietin induces a rapid and transient increase in intracellular Ca 2+ concentration in neuronal cells suggest that erythropoietin plays a neuroprotective role in brain injury caused by hypoxia or ischemia and that erythropoietin-induced Ca 2+ influx from outside of the cells is a critical initial event yielding an enhanced resistance of the neurons to glutamate toxicity.