Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo

Abstract

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.

Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition

“…22 Downstream of these events, activation of both Epo has been demonstrated to be antiapoptotic in other models of neuronal injury both in vitro 38 and in vivo. 39,40 Using a well-characterized model of neonatal hypoxia-ischemia (HI), 41,42 we observed that Epo reduced the infarct volumes by approximately 50% (unpublished observations; manuscript under revision). In this study, we were unable to detect any reduction in the loss of SVZ, GCL or myelination after IR.…”

Erythropoietin Prevents Haloperidol Treatment-Induced Neuronal Apoptosis through Regulation of BDNF

“…In addition, rhEPO has therapeutic advantages over other neurotrophic factors in terms of delivery to their target cells in the brain and clinical tolerability (Abicht and Lochmuller, 1999;Horina et al, 1991). Although there are some concerns regarding the hematopoietic activity of rhEPO, derivatives of rhEPO are being developed that have potent neuroprotective activity with no hematopoietic activity (Erbayraktar et al, 2003).…”

Revisiting the role of erythropoietin for treatment of ocular disorders

“…It has been tested pre-clinically for neuroprotection in animal models for central nervous system-associated disorders such as stroke, spinal cord injury, and others. [82][83][84] This formulation is nonerythropoietic due to its rapid half-life and ideal for use in proliferative retinopathies such as DR. Repeated intravitreal injection of EPO with rapid clearance when indicated clinically would be ideal for proliferative retinopathies in the early stage.…”

“…The brief binding of asialoEPO to EPOR and the specificity of CEPO on retinal neurons may suggest suitable indication for AMD and DR. 31,82,90,105 We foresee that more clinical trials will be conducted to address on the bio-distribution, safety and efficacy of these new derivatives or peptide (peginesatide) 106 before delineating their optimal use in ocular disorders. So far, Hallym University Medical Center is sponsoring a clinical trial (NCT01131533) to determine the intraocular pharmacokinetics following single intravitreal injection of epoietin alfa.…”