Pchelin 2018 IOC130

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Activation of heterodimeric receptor to erythropoietin with its agonist CdEPO regulates brain mitochondrial bioenergetics after local acute ischemia/reperfusion in C57BL/6 mice.

Link: Mitochondr Physiol Network 23.06

Pchelin P, Glyavina M, Loginov P, Shchelchkova N, Mukhina I (2018)

Event: IOC130

Ischemic lesions remain to be one of the main causes of physical disability and mortality worldwide. Furthermore, stroke is known to be followed by mitochondrial dysfunction and impaired cell respiration. Mounting evidence demonstrates that the cytokine hormone erythropoietin (EPO) is capable of activating signaling pathways that increase the brain’s resistance to ischemia/reperfusion stress. After the discovery of EPO’s heteroreceptor that promotes tissue protection [1], a number of attempts were made to develop non-hematopoietic EPO’s derivatives, including CdEPO. However, the precise mechanisms implicated into protective CdEPO effect, notably on brain mitochondria, are still to be elucidated.

The purpose of current research is to elucidate the effect of non-hematopoietic derivative of erythropoietin (CdEPO) on brain mitochondria respiration rate on 4, 10 and 20 day after local acute ischemia/reperfusion in mice.

Male C57BL/6 mice (2 months old, weighing 18-23 g) were used in the study. Local acute ischemia in mice was induced with transient middle cerebral artery occlusion (tMCAO). Following 6 hours after ischemic exposure a fivefold intravenous СdEPO administration was carried out. In a control group the administration of sodium chloride was performed in the same conditions. On 4, 10 and 20 day after reperfusion forebrains of animals were dissected to obtain isolated mitochondria. Bioenergetic studies were carried out using high-resolution respirometry (Oroboros Oxygraph-2k). Significant difference (at least p<0.05) was tested by one-way ANOVA and Holm-Sidak post hoc.

It was revealed that ischemia/reperfusion with tMCAO did not lead to significant alterations in LEAK (glutamate and malate) respiration (Fig. 1 A). Intravenous CdEPO administration following 6 hours after ischemia/reperfusion did not exert any effect on LEAK respiration rate compared to control level. However, on day 20 after reperfusion brain mitochondrial OXPHOS respiration showed a significant decrease by 41% (p=0.01) in the control group compared to intact level (Fig. 1 B). Along with that on day 20 OXPHOS respiration rate was increased by 35% (p=0.027) in the CdEPO group in comparison with control level.

The observed effect of CdEPO on forebrain mitochondrial bioenergetics might be implicated in the realization of protective mechanisms, which was induced by EPO’s heteroreceptor activation, and resulted in postponed improvement of mitochondrial respiration after ischemia/reperfusion. Other effects of CdEPO on different parameters of mitochondrial bioenergetics require further investigation.

Bioblast editor: Kandolf G O2k-Network Lab: RU Nizhny Novgorod Mukhina I

Labels: MiParea: Respiration, Pharmacology;toxicology 

Stress:Ischemia-reperfusion  Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria 

Coupling state: LEAK  Pathway:HRR: Oxygraph-2k 


Figure 1 - Pchelin P.png


Privolzhskiy Research Medical Univ, Nizhny Novgorod, Russia. - ptch.pv@gmail.com


  1. Brines M, Patel NS, Villa P, Brines C, Mennini T, De Paola M, Erbayraktar Z, Erbayraktar S, Sepodes B, Thiemermann C, Ghezzi P, Yamin M, Hand CC, Xie QW, Coleman T, Cerami A (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A 105:10925-30.