Background: Erythropoietin (EPO) and its receptor play a major role in embryonic brain, are weakly expressed in normal postnatal/adult brain and up-regulated upon metabolic stress. EPO protects neurons from hypoxic/ ischemic injury. The objective of this trial is to study the safety and efficacy of recombinant human EPO (rhEPO) for treatment of ischemic stroke in man. Materials and Methods: The trial consisted of a safety part and an efficacy part. In the safety study, 13 patients received rhEPO intravenously (3.3 � 10 4 IU/50 ml/30 min) once daily for the first 3 days after stroke. In the double-blind randomized proof-of-concept trial, 40 patients received either rhEPO or saline. Inclusion criteria were age � 80 years, ischemic stroke within the middle cerebral artery territory confirmed by diffusion-weighted MRI, symptom onset � 8 hr before drug administration, and deficits on stroke scales. The study endpoints were functional outcome at day 30 (Barthel Index, modified Rankin scale), NIH and Scandinavian stroke scales, evolution of

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Erythropoietin therapy for acute stroke is both safe and beneficial.

Erythropoietin, a kidney cytokine regulating haematopoiesis (the production of blood cells), is also produced in the brain after oxidative or nitrosative stress. The transcription factor hypoxia-inducible factor-1 (HIF-1) upregulates EPO following hypoxic stimuli. Here we show that preconditioning with EPO protects neurons in models of ischaemic and degenerative damage due to excitotoxins and consequent generation of free radicals, including nitric oxide (NO). Activation of neuronal EPO receptors (EPORs) prevents apoptosis induced by NMDA (N-methyl-d-aspartate) or NO by triggering cross-talk between the signalling pathways of Janus kinase-2 (Jak2) and nuclear factor-kappaB (NF-kappaB). We show that EPOR-mediated activation of Jak2 leads to phosphorylation of the inhibitor of NF-kappaB (IkappaB), subsequent nuclear translocation of the transcription factor NF-kappaB, and NF-kappaB-dependent transcription of neuroprotective genes. Transfection of cerebrocortical neurons with a dominant interfering form of Jak2 or an IkappaBalpha super-repressor blocks EPO-mediated prevention of neuronal apoptosis. Thus neuronal EPORs activate a neuroprotective pathway that is distinct from previously well characterized Jak and NF-kappaB functions. Moreover, this EPO effect may underlie neuroprotection mediated by hypoxic-ischaemic preconditioning.

Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades.

Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.

/pdf/derivatives-of-erythropoietin-that-are-tissue-protective-but-1r08myafi7.pdf

Derivatives of Erythropoietin That Are Tissue Protective But Not Erythropoietic

https://www.cell.com/trends/neurosciences/pdf/S0166-2236(03)00071-7.pdf

Ischemic tolerance and endogenous neuroprotection

A wide range of insults can trigger axon degeneration, and axons respond with diverse morphology, topology and speed. However, recent genetic, immunochemical, morphological and pharmacological investigations point to convergent degeneration mechanisms. The principal convergence points - poor axonal transport, mitochondrial dysfunction and an increase in intra-axonal calcium - have been identified by rescuing axons with the slow Wallerian degeneration gene (Wld(S)) and studies with blockers of sodium or calcium influx. By understanding how the pathways fit together, we can combine our knowledge of mechanisms, and potentially also treatment strategies, from different axonal disorders.

Axon degeneration mechanisms: commonality amid diversity

Erythropoietin (EPO) promotes neuronal survival after hypoxia and other metabolic insults by largely unknown mechanisms. Apoptosis and necrosis have been proposed as mechanisms of cellular demise, and either could be the target of actions of EPO. This study evaluates whether antiapoptotic mechanisms can account for the neuroprotective actions of EPO. Systemic administration of EPO (5,000 units/kg of body weight, i.p.) after middle-cerebral artery occlusion in rats dramatically reduces the volume of infarction 24 h later, in concert with an almost complete reduction in the number of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling of neurons within the ischemic penumbra. In both pure and mixed neuronal cultures, EPO (0.1–10 units/ml) also inhibits apoptosis induced by serum deprivation or kainic acid exposure. Protection requires pretreatment, consistent with the induction of a gene expression program, and is sustained for 3 days without the continued presence of EPO. EPO (0.3 units/ml) also protects hippocampal neurons against hypoxia-induced neuronal death through activation of extracellular signal-regulated kinases and protein kinase Akt-1/protein kinase B. The action of EPO is not limited to directly promoting cell survival, as EPO is trophic but not mitogenic in cultured neuronal cells. These data suggest that inhibition of neuronal apoptosis underlies short latency protective effects of EPO after cerebral ischemia and other brain injuries. The neurotrophic actions suggest there may be longer-latency effects as well. Evaluation of EPO, a compound established as clinically safe, as neuroprotective therapy in acute brain injury is further supported.

https://www.pnas.org/content/pnas/98/7/4044.full.pdf

Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress

Acetyl-L-carnitine shows neuroprotective and neurotrophic activity in primary culture of rat embryo motoneurons.

Erythropoietin (EPO) promotes neuronal survival after hypoxia and hy other metabolic insults by largely unknown mechanisms. Apoptoro sis and necrosis have been proposed as mechanisms of cellular demise, and either could be the target of actions of EPO. This study wi evaluates whether antiapoptotic mechanisms can account for the ist neuroprotective actions of EPO. Systemic administration of EPO afi (5,000 units/kg of body weight, i.p.) after middle-cerebral artery ph occlusion in rats dramatically reduces the volume of infarction 24 h (Ji later, in concert with an almost complete reduction in the number do of terminal deoxynucleotidyltransferase-mediated dUTP nick-end ac labeling of neurons within the ischemic penumbra. In both pure [P and mixed neuronal cultures, EPO (0.1-10 units/ml) also inhibits an apoptosis induced by serum deprivation or kainic acid exposure. efi Protection requires pretreatment, consistent with the induction of pr a gene expression program, and is sustained for 3 days without the continued presence of EPO. EPO (0.3 units/ml) also protects hipne pocampal neurons against hypoxia-induced neuronal death grn on through activation of extracellular signal-regulated kinases and on protein kinase Akt-1/protein kinase B. The action of EPO is not I limited to directly promoting cell survival, as EPO is trophic but not b mitogenic in cultured neuronal cells. These data suggest that n inhibition of neuronal apoptosis underlies short latency protective effects of EPO after cerebral ischemia and other brain injuries. The a ce

Claudio Pasquali

Papers

Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress

Acetyl-L-carnitine shows neuroprotective and neurotrophic activity in primary culture of rat embryo motoneurons.

Erythropoietin prevents neur cerebral ischemia and metab