Correspondence

Erythropoietin, Glutamate, and Neuroprotection

N Engl J Med 2004; 351:1465-1466September 30, 2004

Article

To the Editor:

Lipton (June 10 issue)1 discusses the possible cellular mechanisms and pathways underlying the neuroprotective effects of erythropoietin in neurologic disorders such as stroke and diabetic neuropathy. Given the key role of glutamate-mediated excitotoxicity in the pathophysiology of stroke and other neurologic conditions, we believe that it is important to address the possibility that a decrease in neuronal glutamate release is a critical mechanism underlying the neuroprotective actions of erythropoietin. For instance, there is evidence that the protective effects of erythropoietin from ischemia-induced neuronal death in cultured hippocampal neurons is mediated by a reduction in glutamate release from synaptic vesicles.2 Such a direct inhibitory effect of erythropoietin on glutamate-mediated excitotoxicity might explain most of the neuroprotective actions of erythropoietin.

Rafael Roesler, Ph.D.
Federal University of Rio Grande do Sul, 90046-900 Porto Alegre, Brazil
rroesler@terra.com.br

Joao Quevedo, M.D., Ph.D.
University of Southern Santa Catarina, 88806-000 Criciúma SC, Brazil

Nadja Schroder, Ph.D.
Catholic University, 90619-900 Porto Alegre RS, Brazil

2 References

1. 1

   Lipton SA. Erythropoietin for neurologic protection and diabetic neuropathy. N Engl J Med 2004;350:2516-2517
   Full Text | Web of Science | Medline

2. 2

   Kawakami M, Sekiguchi M, Sato K, Kozaki S, Takahashi M. Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia. J Biol Chem 2001;276:39469-39475
   CrossRef | Web of Science | Medline

Author/Editor Response

I would like to thank Dr. Roesler and colleagues for suggesting that erythropoietin could decrease glutamate release from neurons and thereby decrease glutamate-induced damage (excitotoxicity).1 My article mentions that erythropoietin can protect neurons from injury due to oxidative and nitrosative stress, which is caused by excitotoxicity,2,3 but the mechanism whereby erythropoietin decreases glutamate release remains unclear. In fact, almost any injury to neurons will result in increased glutamate release because of a calcium influx caused by depolarization of the cell (the transmembrane potential becomes more positive owing to an influx of excessive ions). Hence, if erythropoietin prevents neuronal cell damage in any of a number of ways, it could indirectly decrease glutamate release. Figure 1 in my article outlines the biochemical pathways known to be triggered directly by erythropoietin. I did not have space to delineate downstream events, such as glutamate release, but these events are also of obvious importance to neuronal protection.

Stuart A. Lipton, M.D., Ph.D.
Burnham Institute, La Jolla, CA 92037

3 References

1. 1

   Kawakami M, Sekiguchi M, Sato K, Kozaki S, Takahashi M. Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia. J Biol Chem 2001;276:39469-39475
   CrossRef | Web of Science | Medline

2. 2

   Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway in neurologic disorders. N Engl J Med 1994;330:613-622
   Full Text | Web of Science | Medline

3. 3

   Lipton SA, Choi YB, Pan ZH, et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993;364:626-632
   CrossRef | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Robert E. Schmidt, Dongyan Feng, Qiuling Wang, Karen G. Green, Lisa L. Snipes, Michael Yamin, Michael Brines. (2011) Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy and neuronopathy in Akita (Ins2Akita) diabetic mouse sympathetic ganglia. Experimental Neurology 232:2, 126-135
   CrossRef

2. 2

   Lin Zhu, Han-dong Wang, Xin-guang Yu, Wei Jin, Liang Qiao, Ting-jia Lu, Ze-lan Hu, Jing Zhou. (2009) Erythropoietin prevents zinc accumulation and neuronal death after traumatic brain injury in rat hippocampus: In vitro and in vivo studies. Brain Research 1289, 96-105
   CrossRef

3. 3

   Paul A Lapchak. (2008) Carbamylated erythropoietin to treat neuronal injury: new development strategies. Expert Opinion on Investigational Drugs 17:8, 1175-1186
   CrossRef

4. 4

   M. Chattopadhyay, C. Walter, M. Mata, D. J. Fink. (2008) Neuroprotective effect of herpes simplex virus-mediated gene transfer of erythropoietin in hyperglycemic dorsal root ganglion neurons. Brain 132:4, 879-888
   CrossRef

5. 5

   Robert E. Schmidt, Karen G. Green, Dongyan Feng, Denise A. Dorsey, Curtis A. Parvin, Jin-Moo Lee, Qinlgi Xiao, Michael Brines. (2008) Erythropoietin and its carbamylated derivative prevent the development of experimental diabetic autonomic neuropathy in STZ-induced diabetic NOD-SCID mice. Experimental Neurology 209:1, 161-170
   CrossRef

6. 6

   Hana Malá, Maria Rodriguez Castro, Katrine Dall Jørgensen, Jesper Mogensen. (2007) Effects of Erythropoietin on Posttraumatic Place Learning in Fimbria-Fornix Transected Rats after a 30-Day Postoperative Pause. Journal of Neurotrauma 24:10, 1647-1657
   CrossRef