Effect of recombinant human erythropoietin on cerebral ischemia following experimental subarachnoid hemorrhage

Alafaci, Concetta; Salpietro, Francesco M.; Grasso, Giovanni; Sfacteria, Alessandra; Passalacqua, Marcello; Morabito, Antonino; Tripodo, Eliana; Calapai, Gioacchino; Buemi, Michele; Tomasello, Francesco

doi:10.1016/s0014-2999(00)00691-9

Cited by 109 publications

(64 citation statements)

References 39 publications

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“…Most of the previous experimental studies examining the neuroprotective effects of Epo have administered the drug either before injury or shortly thereafter (Bernaudin et al, 1999;Alafaci et al, 2000;Calapai et al, 2000;Catania et al, 2002;Celik et al, 2002;Gorio et al, 2002;Junk et al, 2002). However, a few studies have directly addressed the issue of time window for neuroprotective effects of Epo after various types of brain injury.…”

Section: Discussionmentioning

confidence: 99%

“…Erythropoietin (Epo) has been shown to have neuroprotective effects against a variety of types of experimental brain injury, including experimental cerebral ischemia (hypoxic/ ischemic injury) (Kumral et al, 2003), global retinal ischemia caused by increasing intraocular pressure (Junk et al, 2002), bilateral carotid occlusion (Catania et al, 2002), middle cerebral artery occlusion (Sirén et al, 2001), focal cerebral ischemia (Bernaudin et al, 1999;Brines et al, 2000), experimental traumatic brain injury (cortical impact injury) (Brines et al, 2000), glutamate neurotoxicity (Morishita et al, 1997), toxin-induced Parkinsonism (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced Parkinsonism) (Genc et al, 2001), spinal cord ischemia (Celik et al, 2002), spinal cord trauma (Gorio et al, 2002), subarachnoid hemorrhage (Alafaci et al, 2000;Grasso, 2001;Springborg et al, 2002), and axotomy (Iwasaki et al, 2002).…”

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confidence: 99%

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Neuroprotection with Erythropoietin Administration Following Controlled Cortical Impact Injury in Rats

Cherian

Goodman²,

Robertson³

2007

J Pharmacol Exp Ther

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This study was designed to determine the effect of erythropoietin (Epo) on cerebral blood flow (CBF), nitric oxide (NO) concentration, and neurological outcome after traumatic brain injury. In one experiment, the hemodynamic effects of Epo were determined after controlled cortical impact injury (CCII) by measuring mean arterial pressure, intracranial pressure, CBF using laser Doppler flowmetry, and brain tissue NO concentrations using an NO electrode. In total, 41 rats were given either Epo (5000 U/kg) or saline s.c. 3 days before injury. In animals pretreated with saline, L-arginine but not D-arginine administration resulted in a significant increase in tissue NO concentrations and an improvement in CBF at the impact site. Likewise, in animals pretreated with Epo, L-arginine but not D-arginine

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Neuroprotection with Erythropoietin Administration Following Controlled Cortical Impact Injury in Rats

Cherian

Goodman²,

Robertson³

2007

J Pharmacol Exp Ther

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“…Erythropoietin (Epo) has been reported to have neuroprotective effects against a variety of types of experimental central nervous system injuries, including neonatal hypoxiaischemia (Aydin et al, 2003), global cerebral ischemia (Catania et al, 2002), middle cerebral artery occlusion (Sirén et al, 2001), experimental traumatic brain injury (TBI) (Brines et al, 2004;Cherian et al, 2007), spinal cord ischemia (Celik et al, 2002), spinal cord trauma (Gorio et al, 2002), and subarachnoid hemorrhage (Alafaci et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Improved Cerebrovascular Function and Reduced Histological Damage with Darbepoietin Alfa Administration after Cortical Impact Injury in Rats

Cherian

Goodman²,

Robertson³

2011

J Pharmacol Exp Ther

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Darbepoetin alfa (darbEpo) is an erythropoietic glycoprotein that activates the erythropoietin receptor. The aim of our study was to determine whether darbEpo is neuroprotective in a cortical impact injury (CII) model and to determine the characteristics of dose response and time window. To better understand the vascular mechanism of darbEpo neuroprotection, the reactivity of cerebral blood flow (CBF) to L-arginine administration was also studied. Rats were given saline or darbEpo from 2.5 to 50 g/kg at 5 min after CII or a dose of 25 g/kg darbEpo at times ranging from 5 min to 24 h after CII. Histological assessment was determined 2 weeks after a severe CII. Other rats were given either darbEpo (25 g/kg) or saline daily for 3 days before injury. Five minutes after severe CII, they were given either L-arginine or D-arginine. Hemodynamic variables were monitored for 2 h after injury. In the dose-response study, darbEpo in doses of 25 and 50 g/kg significantly reduced contusion volume from 39.1 Ϯ 6.7 to 8.1 Ϯ 3.1 and 11.2 Ϯ 6.0 mm 3 , respectively. In the time window study, darbEpo reduced contusion volume when given in a dose of 25 g/kg at 5 min to 6 h after the impact injury. In animals pretreated with darbEpo, the CBF response to L-arginine was significantly greater than in the animals pretreated with saline. These data demonstrate that darbEpo has neuroprotective effects in traumatic brain injury in a dose-and time-dependent manner and that vascular effects of darbEpo may have a role in neuroprotection.

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“…Epo receptors (EpoR) are present on many cell types in brain, and their activation by Epo results in cell-specific effects (8). Stimulation of neurons with recombinant Epo (rEpo) decreases glutamate toxicity (both N-methyl-D-aspartate and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid mediated) (9,10), up-regulates antiapoptotic factors Bcl-x L and Bcl-2 (4,11), and decreases nitric oxide-mediated injury (12)(13)(14). In addition, rEpo preserves blood-brain barrier integrity (15), enhances proliferation/ differentiation of oligodendrocyte precursors (16), and promotes neurogenesis from neural stem cells (17).…”

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confidence: 99%

Erythropoietin Protects Dopaminergic Neurons and Improves Neurobehavioral Outcomes in Juvenile Rats after Neonatal Hypoxia-Ischemia

2005

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Brain injury as a result of hypoxia-ischemia remains a common cause of morbidity and mortality in neonates. No effective therapy is currently available. The hematopoietic cytokine erythropoietin (Epo) provides neuroprotection in many adult models of brain injury and is currently being investigated as a therapeutic agent for human stroke and spinal cord injury. We tested the hypothesis that recombinant Epo (rEpo) would improve neurobehavioral outcomes after neonatal hypoxic-ischemic brain injury. Postnatal day 7 rats underwent right common carotid artery occlusion followed by a 90-min exposure to 8% oxygen. Rats were subsequently treated with rEpo or placebo. Sensory neglect and apomorphine-induced rotation were measured at P27 and P28. Rats were killed at P30, blood was drawn, and the brains were perfusion-fixed for histology and immunohistochemistry. No differences in gross brain injury between rEpo and placebotreated rats were found. Neonatal rEpo treatment protected dopamine neurons as indicated by the preservation of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta and ventral tegmental area. rEpo treatment also improved functional outcomes by reducing sensory neglect and preventing the rotational asymmetry seen in control animals. No differences in hematocrit, white blood cell counts, neutrophil counts, or platelet counts were measured. We observed that rEpo treatment protected mesencephalic dopamine neurons and reduced the degree of behavioral asymmetries at 4 wk of life. On the basis of these findings, we conclude that further studies investigating the safety and efficacy of high-dose rEpo as a neuroprotective strategy are indicated in neonatal models of hypoxic-ischemic brain injury. Abbreviations ADHD, attention-deficit/hyperactivity disorder DA, dopamine Epo, erythropoietin EpoR, erythropoietin receptor HI, hypoxia-ischemia P, postnatal day rEpo, recombinant Epo SNpc, substantia nigra pars compacta TH, tyrosine hydroxylase VTA, ventral tegmental area Perinatal exposure to hypoxia-ischemia (HI) produces brain injury that is a significant source of morbidity and mortality for preterm and term neonates. Neonatal HI exposure initiates a multifactorial cascade that can persist for days, producing injury to multiple brain regions with corresponding motor, behavioral, and cognitive impairments. Although there are currently no effective therapies to ameliorate hypoxic-ischemic brain injury, several useful rodent models of neonatal brain injury are available. Using 7-d-old (P7) rat pups, which are comparable to near-term humans in brain maturity (1), the technique entails unilateral ligation of the common carotid artery and subsequent exposure of the animals to hypoxia (Rice-Vannucci model) (2). This procedure produces permanent unilateral brain injury in multiple regions, with specific impact on the basal ganglia including decreases in striatal dopamine (DA) receptors and increases in striatal DA transporters (3,4). Disruption of dopaminergic neurotransmission is suspect for several de...

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Effect of recombinant human erythropoietin on cerebral ischemia following experimental subarachnoid hemorrhage

Cited by 109 publications

References 39 publications

Neuroprotection with Erythropoietin Administration Following Controlled Cortical Impact Injury in Rats

Neuroprotection with Erythropoietin Administration Following Controlled Cortical Impact Injury in Rats

Improved Cerebrovascular Function and Reduced Histological Damage with Darbepoietin Alfa Administration after Cortical Impact Injury in Rats

Erythropoietin Protects Dopaminergic Neurons and Improves Neurobehavioral Outcomes in Juvenile Rats after Neonatal Hypoxia-Ischemia

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