EPO has multiple positive effects on astrocytes in an experimental model of ischemia

Brain Res. 2023 Mar 1:1802:148207. doi: 10.1016/j.brainres.2022.148207. Epub 2022 Dec 20.

Abstract

Erythropoietin (EPO) has neuroprotective effects in central nervous system injury models. In clinical trials EPO has shown beneficial effects in traumatic brain injury (TBI) as well as in ischemic stroke. We have previously shown that EPO has short-term effects on astrocyte glutamatergic signaling in vitro and that administration of EPO after experimental TBI decreases early cytotoxic brain edema and preserves structural and functional properties of the blood-brain barrier. These effects have been attributed to preserved or restored astrocyte function. Here we explored the effects of EPO on astrocytes undergoing oxygen-glucose-deprivation, an in vitro model of ischemia. Measurements of glutamate uptake, intracellular pH, intrinsic NADH fluorescence, Na,K-ATPase activity, and lactate release were performed. We found that EPO within minutes caused a Na,K-ATPase-dependent increase in glutamate uptake, restored intracellular acidification caused by glutamate and increased lactate release. The effects on intracellular pH were dependent on the sodium/hydrogen exchanger NHE. In neuron-astrocyte co-cultures, EPO increased NADH production both in astrocytes and neurons, however the increase was greater in astrocytes. We suggest that EPO preserves astrocyte function under ischemic conditions and thus may contribute to neuroprotection in ischemic stroke and brain ischemia secondary to TBI.

Keywords: Astrocyte; Erythropoietin; Glutamate; Ischemia; Neuroprotection.

MeSH terms

  • Astrocytes
  • Brain Injuries, Traumatic*
  • Erythropoietin*
  • Glutamic Acid / pharmacology
  • Humans
  • Ischemia
  • Ischemic Stroke*
  • Models, Theoretical
  • NAD
  • Sodium-Potassium-Exchanging ATPase

Substances

  • Sodium-Potassium-Exchanging ATPase
  • NAD
  • Erythropoietin
  • Glutamic Acid