Erythropoietin, Glutamate, and Neuroprotection
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《新英格兰医药杂志》
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
References
Lipton SA. Erythropoietin for neurologic protection and diabetic neuropathy. N Engl J Med 2004;350:2516-2517.
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.
Dr. Lipton replies: 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
References
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.
Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway in neurologic disorders. N Engl J Med 1994;330:613-622.
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.
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
References
Lipton SA. Erythropoietin for neurologic protection and diabetic neuropathy. N Engl J Med 2004;350:2516-2517.
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.
Dr. Lipton replies: 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
References
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.
Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway in neurologic disorders. N Engl J Med 1994;330:613-622.
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.