Erythropoietin: a multimodal neuroprotective agent

Abstract

The tissue protective functions of the hematopoietic growth factor erythropoietin (EPO) are independent of its action on erythropoiesis. EPO and its receptors (EPOR) are expressed in multiple brain cells during brain development and upregulated in the adult brain after injury. Peripherally administered EPO crosses the blood-brain barrier and activates in the brain anti-apoptotic, anti-oxidant and anti-inflammatory signaling in neurons, glial and cerebrovascular endothelial cells and stimulates angiogenesis and neurogenesis. These mechanisms underlie its potent tissue protective effects in experimental models of stroke, cerebral hemorrhage, traumatic brain injury, neuroinflammatory and neurodegenerative disease. The preclinical data in support of the use of EPO in brain disease have already been translated to first clinical pilot studies with encouraging results with the use of EPO as a neuroprotective agent.

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 …”

Developmental Disability in the Young and Postoperative Cognitive Dysfunction in the Elderly After Anesthesia and Surgery: Do Data Justify Changing Clinical Practice?

“…[and] we may eventually be able to manipulate these precursors to improve recovery of function.'' 186,187 In addition to ischemic preconditioning, 188 granulocyte-colony stimulating factor 189 and EPO 176,190,191 appear to be such manipulators, and neurogenesis may be the mechanism of electroconvulsive therapy in patients with depression. 192,193 The old adage that neurogenesis is only for the young was shown to be wrong for rodents in 1965, is known to be wrong for nonhuman primates, and is almost certainly wrong for humans.…”

The Protective Role of Erythropoietin in the Developing Brain

“…A major mechanism of Epo-induced neuroprotection is its ability to prevent apoptosis (Byts & Sirén, 2009;Chen et al, 2007;Chong et al, 2005;Digicaylioglu & Lipton, 2001;Kaindl et al, 2008;Kumral et al, 2006;Ruscher et al, 2002;Sirén et al, 2001;Villa et al, 2003;Weber et al, 2002;Wen et al, 2002;Wu et al, 2007). Other mechanisms of Epo-induced neuroprotection include anti-inflammatory, anti-oxidative, anti-neurotoxic, angiogenic, neurotrophic effects, neural regeneration, prevention from edema and protecting the white matter (Agnello et al, 2002;Kertesz et al, 2004;Kumral et al, 2005a,b;Maiese et al, 2008a;Pankratova et al, 2010;Rabie & Marti, 2008;Shingo et al, 2001;Sifringer et al, 2009Sifringer et al, , 2010Solaroglu et al, 2003;van der Kooij et al, 2008;Wang et al, 2004;Zacharias et al, 2010).…”

“…The reported neurotrophic effects of Epo include the ability to stimulate neurite formation, axonal regrowth, dendritic sprouting, electrical activity and modulate intracellular calcium and neurotransmitter synthesis and release (Byts et al, 2008;Byts & Sirén, 2009;Campana et al, 1998;Kawakami et al, 2000Kawakami et al, , 2001Konishi et al, 1993;Koshimura et al, 1999;Lipton, 2004;Tabira et al, 1995;Tsai et al, 2006;Viviani et al, 2005;Weber et al, 2002;Yamamoto et al, 2000). Epo activates the cAMP response element binding protein (CREB) transcription pathway and increases brain-derived neurotrophic factor (BDNF) expression and production in primary hippocampal neurons, which contributes to neuroprotection (Viviani et al, 2005).…”