Pharmacokinetics of High-Dose Recombinant Erythropoietin in Plasma and Brain of Neonatal Rats

Statler, P.; McPherson, Ronald J.; Bauer, Larry A.; Kellert, Brian; Juul, Sandra E.

doi:10.1203/pdr.0b013e31805341dc

Cited by 129 publications

(117 citation statements)

References 22 publications

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“…Meanwhile, i.p. injection also resulted in a more pronounced penetration into the brain than s.c. injection after HI (34). We administered EPO i.p.…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effect of Erythropoietin on Sensorimotor Function and White Matter After Hypoxia-Ischemia in Neonatal Mice

et al. 2011

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There are mixed reports on the neuroprotective properties of erythropoietin (EPO) in animal models of birth asphyxia. We investigated the effect of EPO on short-and long-term outcome after neonatal hypoxic-ischemic (HI) brain injury in mice and compared the effect of two different dose regimens of EPO. Nine-day-old mice were subjected to HI, and EPO was injected i.p. at 0, 24, and 48 h after HI in a dose of either 5 or 20 kU/kg. Paw preference in the cylinder rearing test (CRT) was used as a measure of sensorimotor function. Only in female mice, administration of EPO at 5 kU/kg but not 20 kU/kg improved sensorimotor function, reduced striatum atrophy and hippocampal lesion volume, and enhanced myelin basic protein (MBP) staining as determined at 4 and 9 wk after HI. In addition, at 72 h after HI, more Ki67 cells were found in the subventricular zone and dentate gyrus after EPO 5 kU/kg treatment, indicating an increase in progenitor cell proliferation. In conclusion, EPO improves sensorimotor function after neonatal HI and protects against striatum atrophy, hippocampus injury, and white matter loss. per 1000 live-born infants and is an important cause of cerebral palsy, epilepsy, and adverse developmental outcome (1,2). Experimental studies in newborn animals with HI showed that antioxidative, anti-inflammatory, and neurotrophic agents are neuroprotective (3,4). However, in clinical studies with newborns with HI encephalopathy, only mild hypothermia showed a modest neuroprotective effect if started within 6 h after birth in asphyxiated term newborns with moderate encephalopathy (5,6).Erythropoietin (EPO), a glycoprotein primarily recognized as a mediator promoting maturation and proliferation of erythroid progenitor cells (7,8), is an attractive drug for this purpose. EPO has been proven to cross the blood-brain barrier after systemic administration at a high dose and to reduce free radical formation and proinflammatory and apoptotic activity in models of brain damage (8 -11). EPO has also been shown to stimulate formation of new neurons because of its actions as a neurotrophic factor (12,13). The effects of EPO are mediated by binding of EPO to its receptor (EPOR), which is present in the brain at relatively high levels in regions known to be sensitive to hypoxia (14,15). Most studies in neonatal animals treated with EPO after HI indeed showed an improved histological outcome (8,16), although our study in rats with neonatal HI brain damage showed no histological improvement (17). However, Spandou et al. (18) reported that in a similar rat model, using a shorter duration of hypoxia, EPO induced effective regeneration of brain tissue.In human studies, no adverse effects of EPO treatment have been reported indicating that EPO is a safe drug for neonates (19). EPO has been increasingly used in preterm infants to treat neonatal anemia or to improve neurodevelopmental outcome, at a low (0.4 kU/kg) or a relatively high dose (3 kU/kg) (19 -21). Furthermore, EPO treatment (0.3-0.5 kU/kg) of perinatally asphyxi...

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“…Meanwhile, i.p. injection also resulted in a more pronounced penetration into the brain than s.c. injection after HI (34). We administered EPO i.p.…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effect of Erythropoietin on Sensorimotor Function and White Matter After Hypoxia-Ischemia in Neonatal Mice

et al. 2011

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“…Even 24 h after a single 5,000 U/kg intraperitoneal dose of EPO, plasma concentrations remain at a high level of >1,000 mU/ml, and levels do not return to baseline before 48 h (37). We therefore believe that a significant amount of apoptosis expected to occur following CLP was prevented with the doses we administered (as seen in the reduced lymphoid apoptosis at 24 h).…”

Section: Erythropoietin In Experimental Sepsismentioning

confidence: 86%

Erythropoietin prevents lymphoid apoptosis but has no effect on survival in experimental sepsis

et al. 2013

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Background: Lymphoid apoptosis in sepsis is associated with poor outcome, and prevention of apoptosis frequently improves survival in experimental models of sepsis. Recently, erythropoietin (EPO) was shown to protect against lipopolysaccharide (LPS)-induced mortality. As cecal ligation and puncture (CLP) is a clinically more relevant model of sepsis, we evaluated the effect of EPO on CLP-induced lymphoid tissue apoptosis and mortality. Methods: Young Wistar rats were subjected to polymicrobial sepsis by CLP. EPO (5,000 U/kg intraperitoneal) was administered 30 min before CLP and then 1 and 4 h after CLP. Spleen, thymus, and small intestine were harvested at 24 h and assessed for apoptosis by terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) and caspase-3 staining. A separate group of animals was followed up for mortality. results: Splenic, thymic, and intestinal apoptosis was increased after CLP; administration of EPO significantly decreased apoptosis as determined by TUNEL and caspase-3 staining. Final survival in the CLP mortality study was 30% in both saline and EPO groups. conclusion: Our results provide the first evidence that EPO attenuates lymphoid apoptosis in the CLP model of sepsis. However, EPO is not associated with a survival benefit in the CLP model of sepsis. s epsis can be described as the systemic maladaptive response of the body to invasion by pathogenic microorganisms (1). It is an important cause of morbidity and mortality in children and adults worldwide. Patients with sepsis often present with evidence of infection, circulatory, and respiratory failure. This presentation is usually caused by an initial, severe proinflammatory response. If appropriate and timely treatment can be instituted, patients may survive this stage; however, an antiinflammatory response frequently follows the proinflammatory phase (2).Apoptosis has been implicated in the development of the anti-inflammatory phase during sepsis (3). Several studies have demonstrated increased lymphocyte apoptosis in animals and humans with sepsis and its relation to poor outcome (2,4-6). Although initial findings were in adults, lymphopenia and apoptosis-associated depletion of lymphoid organs also have a role in sepsis-related death in critically ill children and neonates (7,8).Uptake of apoptotic cells by phagocytic cells leads to production of anti-inflammatory cytokines or anergy, whereas uptake of necrotic cells causes secretion of proinflammatory cytokines. Therefore, in contrast to necrosis, apoptotic cell death does not produce inflammation but rather an immunosuppressive state (9). The importance of apoptosis in sepsis has been revealed by multiple experimental studies that demonstrated that prevention of lymphocyte apoptosis increases survival (10-13).Among the candidates for a therapeutic approach is erythropoietin (EPO), a hematopoietic growth factor shown to have antiapoptotic and cytoprotective effects in both animal and human models of hypoxia-ischemia (14-17). We previously demonstrated that EPO decreases ...

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“…To date, no data have been published on the pharmacokinetics of rEPO in bacterial meningitis. Only very few data are available about the penetration of EPO in the CSF in patients with noninflamed meninges (25) and in the brain tissue of rats after cerebral hypoxia (26). In our rabbit model of E. coli meningitis, we investigated the pharmacokinetics of rEPO and could demonstrate a high penetration rate with a CSF-to-plasma ratio of 0.18 Ϯ 0.07 (mean Ϯ SD) 6 h after injection.…”

Section: Discussionmentioning

confidence: 96%

No Neuroprotective Effect of Erythropoietin Under Clinical Treatment Conditions in a Rabbit Model of Escherichia coli Meningitis

et al. 2007

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Despite effective antibiotic treatment, neuronal injury is frequent among children and adults with bacterial meningitis resulting in a high rate of death and neurologic sequelae. The hematopoietic cytokine erythropoietin (EPO) provides neuroprotection in models of acute and chronic neurologic diseases. We studied whether recombinant EPO (rEPO) reduces neuronal damage in a rabbit model of Escherichia coli meningitis. Inflammation within the central nervous system (CNS) was monitored by measurement of bacterial load, pleocytosis, protein, and lactate in the cerebrospinal fluid (CSF). Neuronal damage was measured by quantification of the density of apoptotic neurons in the hippocampal dentate gyrus and the concentration of the global neuronal destruction marker neuronspecific enolase (NSE) in CSF. To increase clinical relevance, rEPO was applied as adjunctive therapy from the beginning of antibiotic therapy 12 h after infection. EPO treatment applied as an intravenous injection at a dose of 1000 IU/kg body weight resulted in plasma concentrations of 6993 Ϯ 1406 mIU/mL, CSF concentrations of 1291 Ϯ 568 mIU/mL, and a CSF-to-plasma ratio of 0.18 Ϯ 0.07 (mean Ϯ SD) 6 h after injection. Under these treatment conditions, no antiinflammatory or neuroprotective effect of EPO was observed. I n children and adults, bacterial meningitis continues to be associated with high rates of death and neurologic sequelae. Neuronal injury in bacterial meningitis is caused by diverse mechanisms including the local and systemic inflammatory host response to bacterial invasion and direct toxicity of bacterial compounds (1).The hematopoietic cytokine erythropoietin (EPO) is a major component of the endogenous tissue-protective system. In the adult brain, EPO and EPO receptors are constitutively expressed only at a low level but are rapidly up-regulated as a response to metabolic stress of neurons (2) and provide neuroprotection in a multimodal manner including the Jak2 (3) and the NFkB (4) systems. Extrinsic application of human recombinant erythropoietin (rEPO) has been shown to be neuroprotective in various models of acute and chronic neurologic diseases, including ischemic stroke, chronic neuroinflammatory disorders such as experimental autoimmune encephalitis (5), and a rabbit model of subarachnoid hemorrhage (6). It acts in an antiapoptotic (3), antioxidative (7,8), antiinflammatory (9,10), and glutamate-inhibitory (11) manner. Since neuronal injury in bacterial meningitis is mediated by inflammation, reactive oxygen species and toxicity of excitatory amino acids, these properties of rEPO appeared promising with respect to a neuroprotective effect of rEPO in the therapy of this disease. EPO is a body's own hormone and rEPO has been applied for long time in the therapy of different types of anemia. The side effects of rEPO are limited and mainly occur during long-term administration. As bacterial meningitis is an acute infection, a potentially neuroprotective treatment would be administered for a short period and should be wel...

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Pharmacokinetics of High-Dose Recombinant Erythropoietin in Plasma and Brain of Neonatal Rats

Cited by 129 publications

References 22 publications

Beneficial Effect of Erythropoietin on Sensorimotor Function and White Matter After Hypoxia-Ischemia in Neonatal Mice

Beneficial Effect of Erythropoietin on Sensorimotor Function and White Matter After Hypoxia-Ischemia in Neonatal Mice

Erythropoietin prevents lymphoid apoptosis but has no effect on survival in experimental sepsis

No Neuroprotective Effect of Erythropoietin Under Clinical Treatment Conditions in a Rabbit Model of Escherichia coli Meningitis

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