Neuroprotective Effect of Darbepoetin Alfa, a Novel Recombinant Erythropoietic Protein, in Focal Cerebral Ischemia in Rats

Belayev, Ludmila; Khoutorova, Larissa; Zhao, Weizhao; Vigdorchik, Alexey; Belayev, Andrey; Busto, Raul; Magal, Ella; Ginsberg, Myron D.

doi:10.1161/01.str.0000160753.36093.da

Cited by 74 publications

(55 citation statements)

References 25 publications

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“…[21][22][23] We now confirm and significantly extend the available literature with the present findings in that EPO enhances both functional and histological recovery of severely injured skeletal muscle tissue. EPO dampens the initial inflammatory cell reaction and increases nutritive blood supply to tissue.…”

Section: Discussionsupporting

confidence: 89%

Erythropoietin improves functional and histological recovery of traumatized skeletal muscle tissue

Rotter

Menshykova

Winkler

et al. 2008

Journal Orthopaedic Research

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Apart from its hematopoietic effect, erythropoietin (EPO) is known as pleiotropic cytokine with anti-inflammatory and antiapoptotic properties. Here, we evaluated for the first time the EPO-dependent regeneration capacity in an in vivo rat model of skeletal muscle trauma. A myoblast cell line was used to study the effect of EPO on serum deprivation-induced cell apoptosis in vitro. A crush injury was performed to the left soleus muscle in 80 rats treated with either EPO or saline. Muscle recovery was assessed by analysis of contraction capacities. Intravital microscopy, BrdU/laminin double immunohistochemistry and cleaved caspase-3 immunohistochemistry of muscle tissue on days 1, 7, 14, and 42 posttrauma served for assessment of local microcirculation, tissue integrity, and cell proliferation. Serum deprivation-induced myoblast apoptosis of 23.9 AE 1.5% was reduced by EPO to 17.2 AE 0.8%. Contraction force analysis in the EPO-treated animals revealed significantly improved muscle strength with 10-20% higher values of twitch and tetanic forces over the 42-day observation period. EPO-treated muscle tissue displayed improved functional capillary density as well as reduced leukocytic response and consecutively macromolecular leakage over day 14. Concomitantly, muscle histology showed significantly increased numbers of BrdU-positive satellite cells and interstitial cells as well as slightly lower counts of cleaved caspase-3-positive interstitial cells. EPO results in faster and better regeneration of skeletal muscle tissue after severe trauma and goes along with improved microcirculation. Thus, EPO, a compound established as clinically safe, may represent a promising therapeutic option to optimize the posttraumatic course of muscle tissue healing.

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Section: Discussionsupporting

confidence: 89%

Erythropoietin improves functional and histological recovery of traumatized skeletal muscle tissue

Rotter

Menshykova

Winkler

et al. 2008

Journal Orthopaedic Research

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“…6,33,44,[55][56][57][58][59][60][61][62][63][64] Earlier studies used the direct intracerebroventricular route of administration of EPO to demonstrate its potent tissue protective activity in focal and global models of cerebral ischemia. [2][3][4] EPO, as a large, highly glycosylated negatively charged molecule, was not expected to penetrate the blood-brain barrier.…”

Section: Stroke and Cerebral Ischemiamentioning

confidence: 99%

“…Intriguingly, EPO and its derivatives reduce histological damage and improve functional outcome when given as intraperitoneal or even intranasal post-treatment after experimental stroke and hypoxia-ischemia. 33,44,[55][56][57][58][59][60][61][62][63][64]73 A typical example of the functional improvement by EPO in sensorimotor deficits after a focal stroke is presented in Figure 2 (Sirén and Ehrenreich, unpublished own preclinical data in preparation of the "Göttingen EPO Stroke Study," see as follows).…”

Section: Stroke and Cerebral Ischemiamentioning

confidence: 99%

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

et al. 2009

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Summary:The growth factor erythropoietin (EPO) and erythropoietin receptors (EPOR) are expressed in the nervous system. Neuronal expression of EPO and EPOR peaks during brain development and is upregulated in the adult brain after injury. Peripherally administered EPO, and at least some of its variants, cross the blood-brain barrier, stimulate neurogenesis, neuronal differentiation, and activate brain neurotrophic, antiapoptotic, anti-oxidant and anti-inflammatory signaling. These mechanisms underlie their tissue protective effects in nervous system disorders. As the tissue protective functions of EPO can be separated from its stimulatory action on hematopoiesis, novel EPO derivatives and mimetics, such as asialo-EPO and carbamoylated EPO have been developed. While the therapeutic potential of the novel EPO derivatives continues to be characterized in preclinical studies, the experimental findings in support for the use of recombinant human (rh)EPO in human brain disease have already been translated to clinical studies in acute ischemic stroke, chronic schizophrenia, and chronic progressive multiple sclerosis. In this review article, we assess the studies on EPO and, in particular, on its structural or functional variants in experimental models of nervous system disorders, and we provide a short overview of the completed and ongoing clinical studies testing EPO as neuroprotective/neuroregenerative treatment option in neuropsychiatric disease.

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“…Infants were randomized in masked fashion to 1 of 3 groups: Epo, 400 U/kg, given subcutaneously 3 times a week (Monday, Wednesday, and Friday); Darbe, 10 mg/kg, given subcutaneously once a week, 14,15 with sham dosing 2 other times per week; or placebo, consisting of 3 sham doses per week. The study drug was brought to the bedside in a closed container, and injections were shielded behind screens and out of earshot from caregivers and parents.…”

Section: Dosing Of Study Drugmentioning

confidence: 99%

“…15,[33][34][35][36][37][38][39][40][41] In addition to stimulating erythropoiesis, ESAs are protective in the developing brain, making it possibly beneficial for very premature infants who are at risk for intraventricular hemorrhage, hypoxicischemic injury, and developmental delay. 37 The neuroprotective mechanisms of ESAs include decreased neuronal apoptosis, decreased inflammation, increased neurogenesis, promotion of oligodendrocyte differentiation and maturation, and improved white matter survival.…”

Section: Figurementioning

confidence: 99%

A Randomized, Masked, Placebo-Controlled Study of Darbepoetin Alfa in Preterm Infants

Ohls¹,

Christensen

Kamath‐Rayne

et al. 2013

Pediatrics

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BACKGROUND: A novel erythropoiesis stimulating agent (ESA), darbepoetin alfa (Darbe), increases hematocrit in anemic adults when administered every 1 to 3 weeks. Weekly Darbe dosing has not been evaluated in preterm infants. We hypothesized that infants would respond to Darbe by decreasing transfusion needs compared with placebo, with less-frequent dosing than erythropoietin (Epo). METHODS: Preterm infants 500 to 1250 g birth weight and ≤48 hours of age were randomized to Darbe (10 μg/kg, 1 time per week subcutaneously), Epo (400 U/kg, 3 times per week subcutaneously) or placebo (sham dosing) through 35 weeks’ gestation. All received supplemental iron, folate, and vitamin E, and were transfused according to protocol. Transfusions (primary outcome), complete blood counts, absolute reticulocyte counts (ARCs), phlebotomy losses, and adverse events were recorded. RESULTS: A total of 102 infants (946 ± 196 g, 27.7 ± 1.8 weeks’ gestation, 51 ± 25 hours of age at first dose) were enrolled. Infants in the Darbe and Epo groups received significantly fewer transfusions (P = .015) and were exposed to fewer donors (P = .044) than the placebo group (Darbe: 1.2 ± 2.4 transfusions and 0.7 ± 1.2 donors per infant; Epo: 1.2 ± 1.6 transfusions and 0.8 ± 1.0 donors per infant; placebo: 2.4 ± 2.9 transfusions and 1.2 ± 1.3 donors per infant). Hematocrit and ARC were higher in the Darbe and Epo groups compared with placebo (P = .001, Darbe and Epo versus placebo for both hematocrit and ARCs). Morbidities were similar among groups, including the incidence of retinopathy of prematurity. CONCLUSIONS: Infants receiving Darbe or Epo received fewer transfusions and fewer donor exposures, and fewer injections were given to Darbe recipients. Darbepoetin and Epo successfully serve as adjuncts to transfusions in maintaining red cell mass in preterm infants.

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Neuroprotective Effect of Darbepoetin Alfa, a Novel Recombinant Erythropoietic Protein, in Focal Cerebral Ischemia in Rats

Cited by 74 publications

References 25 publications

Erythropoietin improves functional and histological recovery of traumatized skeletal muscle tissue

Erythropoietin improves functional and histological recovery of traumatized skeletal muscle tissue

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

A Randomized, Masked, Placebo-Controlled Study of Darbepoetin Alfa in Preterm Infants

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