Erythropoietin Selectively Attenuates Cytokine Production and Inflammation in Cerebral Ischemia by Targeting Neuronal Apoptosis

Abstract

Ischemic brain injury resulting from stroke arises from primary neuronal losses and by inflammatory responses. Previous studies suggest that erythropoietin (EPO) attenuates both processes. Although EPO is clearly antiapoptotic for neurons after experimental stroke, it is unknown whether EPO also directly modulates EPO receptor (EPO-R)–expressing glia, microglia, and other inflammatory cells. In these experiments, we show that recombinant human EPO (rhEPO; 5,000 U/kg body weight, i.p.) markedly reduces astrocyte activation and the recruitment of leukocytes and microglia into an infarction produced by middle cerebral artery occlusion in rats. In addition, ischemia-induced production of the proinflammatory cytokines tumor necrosis factor, interleukin 6, and monocyte chemoattractant protein 1 concentration is reduced by >50% after rhEPO administration. Similar results were also observed in mixed neuronal-glial cocultures exposed to the neuronal-selective toxin trimethyl tin. In contrast, rhEPO did not inhibit cytokine production by astrocyte cultures exposed to neuronal homogenates or modulate the response of human peripheral blood mononuclear cells, rat glial cells, or the brain to lipopolysaccharide. These findings suggest that rhEPO attenuates ischemia-induced inflammation by reducing neuronal death rather than by direct effects upon EPO-R–expressing inflammatory cells.

Protective effect of erythropoietin against 1-methyl-4-phenylpyridinium-induced neurodegenaration in PC12 cells

“…Studies in vitro provided informations related to the molecular pathways involved in EPO action. These data showed that EPO may have a direct protective role against a variety of neurotoxic insults, such as hypoxic conditions [11] , glutamate toxicity [12] , free-radical injury [13] , and exposure to neurotoxicants [14] . In addition, EPO receptor is abundantly expressed in adult dopaminergic neurons [15] , suggesting a direct effect of EPO on neurons.…”

Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

“…In this study, we demonstrated that EPO treatment decreased the activated microglia expression in the cortex of injured brain. EPO also decreased activated microglia expression in autoimmune encephalomyelitis, Alzheimer disease, and ischemic brain injury (Assaraf et al., 2007; Villa et al., 2003; Yuan et al., 2008). …”

“…Recombinant human EPO was provided by Roche Diagnostics GmbH (Mannheim, Germany). At 1 hr and 1, 2, and 3 days after FPI, mice were injected intraperitoneally with EPO (5000 U/kg) or equal volume of sterile saline (Chen et al., 2007; Villa et al., 2003). …”

“…Erythropoietin receptor (EPOR) is expressed by a variety of nonhematopoietic cell types such as vascular smooth muscle cells, myocardial cells, brain capillary endothelial cells, and neurons (Acheson, Richards, & de Wit, 2007; Bernaudin et al., 1999; Cianferotti & Brandi, 2014; Wright et al., 2004). EPO can alleviate motor and cognitive deficit, axonal pathology, and neuroinflammation in the models of cerebral ischemia (Villa et al., 2003), experimental autoimmune encephalomyelitis (EAE) (Yuan et al., 2008), and diffuse axonal injury (DAI) (Hellewell, Yan, Alwis, Bye, & Morganti‐Kossmann, 2013). Immune/inflammatory responses play an important role in the pathological process of secondary brain injury.…”

Revisiting the role of erythropoietin for treatment of ocular disorders

“…Recent studies subjected to the use of EPO in various types of ocular disorders have reported on its neuroprotective functions such as antiapoptotic, 15,[19][20][21] anti-oxidant, [22][23][24][25] and anti-inflammatory properties. [26][27][28] However, their roles in the pathogenesis of ocular disorders were unclear. The use of EPO for the treatment of ocular disorders has raised concerns and doubts as to whether they aggravate pathogenicity or provide protection to counter the insults to the eye.…”