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Published on: November 20, 2015
Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity
Mark Dzietko1, Ursula Felderhoff-Mueser, Marco Sifringer
1Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany.
Insights
Recombinant erythropoietin (rEPO) offers neuroprotection against NMDA receptor antagonist-induced brain damage in neonatal rats. This study shows rEPO can mitigate apoptosis and enhance neurotrophic signaling pathways, suggesting a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- N-methyl-D-aspartate (NMDA) receptor antagonists can cause apoptotic neurodegeneration in developing brains.
- Pediatric anesthesia and sedation frequently involve NMDA receptor antagonists, necessitating neuroprotective strategies.
Purpose of the Study:
- To investigate the neuroprotective potential of recombinant erythropoietin (rEPO) against NMDA receptor antagonist-induced neurotoxicity in neonatal rats.
- To elucidate the mechanisms underlying rEPO's neuroprotective effects.
Main Methods:
- Neonatal rats were administered the NMDA receptor antagonist MK801 to induce apoptosis.
- Recombinant erythropoietin (rEPO) was coadministered to assess its neuroprotective effects.
- Gene expression (mRNA) of erythropoietin (EPO), EPO receptor, brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) were analyzed.
- Protein phosphorylation levels of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and Akt were measured.
Main Results:
- MK801 exposure induced apoptosis in the neonatal rat forebrain, particularly in the cortex and thalamus.
- MK801 reduced mRNA levels of EPO and its receptor, suggesting a role for endogenous EPO deficiency.
- Coadministration of rEPO provided significant neuroprotection (50%) against MK801-induced damage.
- rEPO partially restored MK801-induced reductions in BDNF and GDNF mRNA levels.
- rEPO prevented the decrease in phosphorylated ERK1/2 and Akt levels caused by MK801.
Conclusions:
- Recombinant erythropoietin (rEPO) demonstrates significant neuroprotective effects against NMDA receptor antagonist-induced neurotoxicity in developing rat brains.
- rEPO's protective mechanism involves the enhancement of neurotrophin-associated signaling pathways, including BDNF, GDNF, ERK1/2, and Akt.
- These findings suggest that rEPO could be a valuable adjunctive therapy to mitigate neurodevelopmental risks associated with NMDA receptor antagonist use in pediatric clinical practice.
Abstract:
Pharmacological blockade of NMDA receptor function induces apoptotic neurodegeneration in the developing rat brain. However, the use of NMDA receptor antagonists as anesthetics and sedatives represents a difficult-to-avoid clinical practice in pediatrics. This warrants the search for adjunctive neuroprotective measures that will prevent or ameliorate neurotoxicity of NMDA receptor antagonists. The NMDA receptor antagonist MK801 triggered apoptosis in the neonatal rat forebrain, most notably in cortex and thalamus. MK801 exposure reduced mRNA levels of erythropoietin (EPO) and the EPO receptor, suggesting that loss of endogenous EPO activity may contribute to MK801-induced apoptosis. Coadministration of recombinant EPO (rEPO) conferred 50% neuroprotection, partially restored MK801-induced reduction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mRNA, and prevented decreased phosphorylation levels of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and Akt. These observations indicate that rEPO partly rescues newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways.
