Erythropoietin protects against brain ischemic injury by inhibition of nitric oxide formation

Calapai, Gioacchino; Marciano, Maria Concetta; Corica, Francesco; Allegra, Alessandro; Parisi, Antonio; Frisina, N; Caputi, Achille P.; Buemi, Michele

doi:10.1016/s0014-2999(00)00466-0

Cited by 220 publications

(155 citation statements)

References 38 publications

Supporting

Mentioning

141

Contrasting

Unclassified

Order By: Relevance

“…Additional evidence has also shown widespread efficacy of rhEPO in injury models of the spinal cord (5,6), retina (7), and the heart (8). Mechanistically, EPO acts in a coordinated fashion at multiple levels, including limiting the production of tissue-injuring molecules [e.g., reactive oxygen species and glutamate (9)(10)(11)], reversal of vasospasm (12,13), attenuation of apoptosis (5,10,14,15), modulation of inflammation (4,16), and recruitment of stem cells (17). A recent clinical trial supports the relevance of these animal models for human disease by demonstrating significant improvement in outcome of stroke patients who were administered rhEPO intravenously within 8 h of the onset of symptoms (18).…”

mentioning

confidence: 99%

Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo

Erbayraktar

Grasso

Sfacteria

et al. 2003

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

410

322

View full text Add to dashboard Cite

Erythropoietin (EPO) is a tissue-protective cytokine preventing vascular spasm, apoptosis, and inflammatory responses. Although best known for its role in hematopoietic lineages, EPO also affects other tissues, including those of the nervous system. Enthusiasm for recombinant human erythropoietin (rhEPO) as a potential neuroprotective therapeutic must be tempered, however, by the knowledge it also enlarges circulating red cell mass and increases platelet aggregability. Here we examined whether erythropoietic and tissue-protective activities of rhEPO might be dissociated by a variation of the molecule. We demonstrate that asialoerythropoietin (asialoEPO), generated by total enzymatic desialylation of rhEPO, possesses a very short plasma half-life and is fully neuroprotective. In marked contrast with rhEPO, this molecule at doses and frequencies at which rhEPO exhibited erythropoiesis, did not increase the hematocrit of mice or rats. AsialoEPO appeared promptly within the cerebrospinal fluid after i.v. administration; intravenously administered radioiodine-labeled asialoEPO bound to neurons within the hippocampus and cortex in a pattern corresponding to the distribution of the EPO receptor. Most importantly, asialoEPO exhibits a broad spectrum of neuroprotective activities, as demonstrated in models of cerebral ischemia, spinal cord compression, and sciatic nerve crush. These data suggest that nonerythropoietic variants of rhEPO can cross the blood–brain barrier and provide neuroprotection.

show abstract

mentioning

confidence: 99%

Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo

Erbayraktar

Grasso

Sfacteria

et al. 2003

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

410

322

View full text Add to dashboard Cite

show abstract

“…The mechanism of this vascular effect of rHuEPO appears to depend on the modulation of inducible nitric oxide synthase activity (Squadrito et al, 1999). Because one mechanism explaining the neuroprotective effect of rHuEPO has been shown to depend on inhibition of nitric oxide production (Calapai et al, 2000), it is reasonable to hypothesize that similar mechanisms may be relevant after TBI. Furthermore, inflammatory cells are involved in the late damage that occurs to the oligodendrocytes that provide brain degeneration (Leinhase et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Processes occurring in the early stage after TBI, such as release of glutamate, lactate, potassium, calcium, free oxygen radicals, histamine, and kinins by injured cells, seem to be more relevant in the pathophysiological mechanisms underlying brain damage following TBI (Unterberg et al, 2004). In this regard, EPO administration has been associated with protection from glutamate toxicity by activation of calcium channels (Sakanaka et al, 1998), production of antioxidant enzymes in neurons (Koshimura et al, 1999), and reduction of the NO toxicity in neurons (Calapai et al, 2000;Sakanaka et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by erythropoietin administration after experimental traumatic brain injury

et al. 2007

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…The hormone inhibits nitric oxide formation in brain tissue after injury and downregulates nitric oxide synthase expression in cultured human endothelial cells. 48,49 EPO may also have an indirect effect on ROS availability. It is well-known that iron plays an important role in bleomycin-induced cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin ameliorates chemotherapy‐induced fibrosis of the lungs in a preclinical murine model

Sigounas

Salleng

Mehlhop

et al. 2008

Intl Journal of Cancer

View full text Add to dashboard Cite

Organ toxicity induced by chemotherapeutic drugs is a serious obstacle in the effective treatment of patients suffering from cancer and autoimmune disease. A strong association exists between pulmonary toxicity, particularly fibrosis, and chemotherapeutic drugs. Attempts have been made to identify compounds capable of suppressing fibrosis. In addition to its erythropoietic activity, erythropoietin (EPO) has been shown to have effects on nonhemopoietic cells. Therefore, we postulated that EPO may exert beneficial effects on lung tissue during chemotherapy. To test our hypothesis, we investigated pulmonary changes caused by bleomycin, a fibrosis‐inducing agent, in animals treated with the drug alone and in combination with EPO. Fibrosis, cellular alterations and structural changes were assayed by blind analysis of the lung sections. A 6‐fold decrease in the number of prominent endothelial cells—suspected to be indicative of cellular activation and inflammatory response—was observed in lung sections derived from mice treated with bleomycin and EPO compared to animals injected with bleomycin alone (p < 0.008). Additionally, there was twice the number of ICAM1‐positive endothelial cells in animals treated with bleomycin alone compared with the number in the bleomycin and EPO‐treated group (p < 0.05). Alveolar mononuclear phagocytic hyperplasia was reduced by as much as 100% in animals treated with bleomycin and EPO compared to animals treated with bleomycin alone (p < 0.03). Finally, a 5‐fold decrease in interstitial fibrosis was observed in lung sections obtained from animals treated with bleomycin and EPO (p < 0.02). We conclude that EPO can ameliorate drug‐induced fibrosis and endothelial damage caused by chemotherapeutic agents. © 2008 Wiley‐Liss, Inc.

show abstract

Erythropoietin protects against brain ischemic injury by inhibition of nitric oxide formation

Cited by 220 publications

References 38 publications

Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo

Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo

Neuroprotection by erythropoietin administration after experimental traumatic brain injury

Erythropoietin ameliorates chemotherapy‐induced fibrosis of the lungs in a preclinical murine model

Contact Info

Product

Resources

About