Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage

Grasso, Giovanni; Buemi, Michele; Alafaci, Concetta; Sfacteria, Alessandra; Passalacqua, Marcello; Sturiale, Alessio; Calapai, Gioacchino; Vico, Gionata De; Piedimonte, Giuseppe; Salpietro, Francesco M.; Tomasello, Francesco

doi:10.1073/pnas.082097299

Cited by 172 publications

(118 citation statements)

References 41 publications

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“…Others subjected rats to bilateral transection of the fimbria-fornix and rHuEPO treatment allowed a better posttraumatic functional recovery (Mogensen et al, 2004). We have previously demonstrated that rHuEPO prevented cognition impairment in a gerbil transient brain ischemia model (Catania et al, 2002) and neurological dysfunction following experimental subarachnoid hemorrhage in rabbits (Grasso et al, 2002a). These studies and the present findings suggest that the neuroprotective effects exerted by rHuEPO administration in models of brain damage are associated with the maintenance of neurological functions.…”

Section: Discussionsupporting

confidence: 77%

“…Expression of EPOR in brain capillary endothelial cells and the ability of systemically administered EPO to cross the BBB have been reported in vivo (Brines et al, 2000;Grasso et al, 2002a). Furthermore, it has been suggested that, after systemic administration, rHuEPO may be transported across the BBB by a specific receptormediated mechanism (Brines et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, it is well known that TBI is associated with an early loss of vascular autoregulation leading to the development of vascular hyperpermeability and tissue edema that ultimately cause neuronal degeneration (Unterberg et al, 2004). In preclinical injury models of cerebral vasospasm induced by subarachnoid hemorrhage (Grasso et al, 2002a;Springborg et al, 2002) it has been shown that EPO can reverse vascular spasm thus providing neuroprotection. The mechanism of this vascular effect of rHuEPO appears to depend on the modulation of inducible nitric oxide synthase activity (Squadrito et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotection by erythropoietin administration after experimental traumatic brain injury

et al. 2007

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A large body of evidence indicates that the hormone erythropoietin (EPO) exerts beneficial effects in the central nervous system (CNS). To date, EPO's effect has been assessed in several experimental models of brain and spinal cord injury. This study was conducted to validate whether treatment with recombinant human EPO (rHuEPO) would limit the extent of injury following experimental TBI. Experimental TBI was induced in rats by a cryogenic injury model. rHuEPO or placebo was injected intraperitoneally immediately after the injury and then every 8 h until 2 or 14 days. Forty-eight hours after injury brain water content, an indicator of brain edema, was measured with the wet-dry method and blood-brain barrier (BBB) breakdown was evaluated by assay of Evans blue extravasation. Furthermore, extent of cerebral damage was assessed. Administration of rHuEPO markedly improved recovery from motor dysfunction compared with placebo group (P < 0.05). Brain edema was significantly reduced in the cortex of the EPO-treated group relative to that in the placebo-treated group (80.6 ± 0.3% versus 91.8% ± 0.8% respectively, P < 0.05). BBB breakdown was significantly lower in EPO-treated group than in the placebo-treated group (66.2 ± 18.7 μg/g versus 181.3 ± 21 μg/g, respectively, P < 0.05). EPO treatment reduced injury volume significantly compared with placebo group (17.4 ± 5.4 mm3 versus 37.1 ± 5.3 mm3, P < 0.05). EPO, administered in its recombinant form, affords significant neuroprotection in experimental TBI model and may hold promise for future clinical applications.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Neuroprotection by erythropoietin administration after experimental traumatic brain injury

et al. 2007

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“…Studies in humans and in experimental diabetes have shown a reduced nerve blood flow and endoneurial hypoxia in the peripheral nerves (29), and rhEPO was reported to ameliorate neurovascular dysfunction in models of subarachnoid hemorrhage and spinal cord injury (38,39). In the neurovascular Fig.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin both protects from and reverses experimental diabetic neuropathy

Bianchi

Büyükakıllı

Brines

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

235

179

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Tail-nerve conduction velocities (NCV) was assessed at 5 and 11 weeks for the preventive and therapeutic schedule, respectively. Compared to nondiabetic rats, NCV was 20% lower after 5 weeks in the STZ group, and this decrease was attenuated 50% by rhEPO. Furthermore, the reduction of Na ؉ ,K ؉ -ATPase activity of diabetic nerves (by 55%) was limited to 24% in the rhEPO-treated group. In the therapeutic schedule, NCV was reduced by 50% after 11 weeks but by only 23% in the rhEPO-treated group. rhEPO treatment attenuated the decrease in compound muscle action potential in diabetic rats. In addition, rhEPO treatment was associated with a preservation of footpad cutaneous innervation, as assessed by protein gene product 9.5 immunostaining. Diabetic rats developed alterations in mechanical and thermal nociception, which were partially reversed by rhEPO given either in a preventative or therapeutic manner. These observations suggest that administration of rhEPO or its analogues may be useful in the treatment of diabetic neuropathy.

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“…Other studies performed in the CNS have also identified critical vascular effects of rhEPO, which act to maintain adequate tissue perfusion, and, in this manner, markedly limit injury, such as the prevention of delayed ischemia after subarachnoid hemorrhage (14). These beneficial vascular effects are not limited to the brain, however, as rhEPO dramatically improves survival in a rat model of septic shock induced by splanchnic artery occlusion by means of a direct inhibition of inducible nitric oxide synthetase (iNOS) activity by peritoneal macrophages (15).…”

Section: Maintained In Vitromentioning

confidence: 98%

Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling

Calvillo

Latini

Kajstura

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

555

429

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Erythropoietin (EPO), originally identified for its critical hormonal role in promoting erythrocyte survival and differentiation, is a member of the large and diverse cytokine superfamily. Recent studies have identified multiple paracrine͞autocrine functions of EPO that coordinate local responses to injury by maintaining vascular autoregulation and attenuating both primary (apoptotic) and secondary (inflammatory) causes of cell death. Experimental evidence also supports a role for EPO in repair and regeneration after brain and spinal cord injury, including the recruitment of stem cells into the region of damage. Tissue expression of the EPO receptor is widespread, especially during development, and includes the heart. However, it is currently unknown as to whether EPO plays a physiological function in adult myocardial tissue. We have assessed the potential protective role of EPO in vitro with adult rat cardiomyocytes, and in vivo in a rat model of myocardial infarction with reperfusion. The results show that EPO markedly prevents the apoptosis of cultured adult rat myocardiocytes subjected to 28 h of hypoxia (Ϸ3% normal oxygen). Additional studies employing a rat model of coronary ischemia-reperfusion showed that the administration of recombinant human EPO (5,000 units͞kg of body weight; i.p. daily for 7 days) reduces cardiomyocyte loss by Ϸ50%, an extent sufficient to normalize hemodynamic function within 1 week after reperfusion. These observations not only suggest a potential therapeutic role for recombinant human EPO in the treatment of myocardial ischemia and infarction by preventing apoptosis and attenuating postinfarct deterioration in hemodynamic function, but also predict that EPO is likely a tissue-protective cytokine in other organs as well.

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Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage

Cited by 172 publications

References 41 publications

Neuroprotection by erythropoietin administration after experimental traumatic brain injury

Neuroprotection by erythropoietin administration after experimental traumatic brain injury

Erythropoietin both protects from and reverses experimental diabetic neuropathy

Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling

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