Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

Abstract

Summary:The growth factor erythropoietin (EPO) and erythropoietin receptors (EPOR) are expressed in the nervous system. Neuronal expression of EPO and EPOR peaks during brain development and is upregulated in the adult brain after injury. Peripherally administered EPO, and at least some of its variants, cross the blood-brain barrier, stimulate neurogenesis, neuronal differentiation, and activate brain neurotrophic, antiapoptotic, anti-oxidant and anti-inflammatory signaling. These mechanisms underlie their tissue protective effects in nervous system disorders. As the tissue protective functions of EPO can be separated from its stimulatory action on hematopoiesis, novel EPO derivatives and mimetics, such as asialo-EPO and carbamoylated EPO have been developed. While the therapeutic potential of the novel EPO derivatives continues to be characterized in preclinical studies, the experimental findings in support for the use of recombinant human (rh)EPO in human brain disease have already been translated to clinical studies in acute ischemic stroke, chronic schizophrenia, and chronic progressive multiple sclerosis. In this review article, we assess the studies on EPO and, in particular, on its structural or functional variants in experimental models of nervous system disorders, and we provide a short overview of the completed and ongoing clinical studies testing EPO as neuroprotective/neuroregenerative treatment option in neuropsychiatric disease.

Widespread Expression of Erythropoietin Receptor in Brain and Its Induction by Injury

“…This experiment served two purposes: to recover defined cells that carry human EPOR in brain sections and to confirm injury-induced endogenous EpoR expression, since in earlier work, we had proposed upregulation of EPOR upon injury (6). At 24 h after injection of medium only (stab wound), we saw cells with strong ctEPOR-AB signal near the injection site ( Figure 4E).…”

Targeting Astrocytes for Stroke Therapy

“…2D). [101][102][103] To harness the restorative power of EPO in stroke, it is important to examine the mechanisms by which the temporal expression of endogenous EPO may be enhanced in astrocytes after stroke. Instead of direct administration of EPO, it may be more beneficial to avoid its potential systemic side effects by administering small molecules that can induce endogenous EPO …”

The neuroprotective and neurorescue effects of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson’s disease

“…Importantly, carbamylated erythropoietin (CEPO) can also cross the blood-brain barrier (BBB) in rats and humans, as EPO can (Brines et al, 2000;Ehrenreich et al, 2004;Verdonck et al, 2007;Siren et al, 2009;Bouzat et al, 2011).…”