Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons

Abstract

Erythropoietin receptor (EpoR) binding mediates neuroprotection by endogenous Epo or by exogenous recombinant human (rh)Epo.The level of EpoR gene expression may determine tissue responsiveness to Epo. Thus, harnessing the neuroprotective power of Epo requires an understanding of the Epo-EpoR system and its regulation. We tested the hypothesis that neuronal expression of EpoR is required to achieve optimal neuroprotection by Epo. The ventral limbic region (VLR) in the rat brain was used because we determined that its neurons express minimal EpoR under basal conditions, and they are highly sensitive to excitotoxic damage, such as occurs with pilocarpine-induced status epilepticus (Pilo-SE). We report that (i) EpoR expression is significantly elevated in nearly all VLR neurons when rats are subjected to 3 moderate hypoxic exposures, with each separated by a 4-day interval; (ii) synergistic induction of EpoR expression is achieved in the dorsal hippocampus and neocortex by the combination of hypoxia and exposure to an enriched environment, with minimal increased expression by either treatment alone; and (iii) rhEpo administered after Pilo-SE cannot rescue neurons in the VLR, unless neuronal induction of EpoR is elicited by hypoxia before Pilo-SE. This study thus demonstrates using environmental manipulations in normal rodents, the strict requirement for induction of EpoR expression in brain neurons to achieve optimal neuroprotection. Our results indicate that regulation of EpoR gene expression may facilitate the neuroprotective potential of rhEpo.hypoxia ͉ environmental enrichment ͉ epilepsy ͉ limbic system ͉ enviromimetic

Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

“…As previously mentioned (Sanchez et al 2009), overexpression of Epo-R is necessary for a successful treatment with exogenously administered rHu-Epo. It was also demonstrated that MDR-1 gene overexpression could cause an impairment of brain hypoxia treatment with conventional drugs (Dohgu et al 2007;Xiao-Dong et al 2008).…”

“…Interestingly, it was recently demonstrated that a single hypoxic exposure (1 h) has no effect on the Epo-R transcript basal levels in neurons immediately after hypoxia, but repetitive hypoxic stimulus can increase [85% the Epo-R transcript level (Sanchez et al 2009). In addition, animals exposed to an experimental model of sleep apnea by intermittent hypoxia showed a persistence of elevated HIF-1a in hippocampal neurons (Aviles-Reyes et al 2010).…”

“…Bernaudin et al (1999) have reported that intracerebroventricular application of exogenous rHu-Epo, 24 h before cerebral ischemia induction, protected against the brain infarct in mice. As elevated expressions of Epo-R in neurons are required for optimal neuroprotection by erythropoietin (Sanchez et al 2009), it is possible that this required high expression of Epo-R, could be activated only if an also high concentration of Epo is produced at the surrounding area. These data indicate that Epo/Epo-R system, could be a plastic endogenous mechanism that continuously modifies their activity according with fluctuations or reduction in the brain blood flow and/or metabolic cells requirements.…”

Neurotrophic paths in the treatment of depression

“…Erythropoietin and its receptors are abundant in the developing brain and persist in the adult hypothalamus, hippocampus and neocortex. 25 Unlike BDNF, EPO crosses the blood-brain barrier 26 to impart neuroprotective effects, and EPO was found to have such actions in models of stroke and traumatic brain injury. 27 Indeed, EPO is already routinely used to help repopulate immune cells following chemotherapy and generally is considered to be well tolerated and safe, although careful titration of doses is essential given its ability to mobilize large numbers of red blood cells that could have negative vascular effects.…”

“…30 Perhaps most importantly in regard to neuroplasticity and depression, EPO may increase BDNF expression and adult hippocampal neurogenesis 31 and hippocampal EPO levels were elevated after antidepressant or electroconvulsive shock treatments. 25,30 Thus, EPO could promote antidepressant effects by inducing BDNF expression or alternatively, by directly stimulating trophic pathways involving phosphatidylinositol-3-kinase (PI3-K), Akt/protein kinase-B, MAP kinases and STAT5. 32 It is also possible that EPO-induced BDNF could act synergistically with exogenously applied EPO to reinforce antidepressant-like actions, since both factors act through PI3-K and MAP kinase pathways.…”