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Research ArticleBEHAVIORAL PHARMACOLOGY

Nitric-Oxide Synthase Mediates the Ability of Darbepoetin Alfa to Attenuate Pre-Existing Spatial Working Memory Deficits in Rats Subjected to Transient Global Ischemia

Michel L. Samson, Kosuke Kajitani and George S. Robertson
Journal of Pharmacology and Experimental Therapeutics May 2010, 333 (2) 437-444; DOI: https://doi.org/10.1124/jpet.110.165530
Michel L. Samson
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Kosuke Kajitani
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George S. Robertson
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Abstract

Erythropoietin has been reported to improve the behavioral performance of healthy mice in tests thought to depend on synaptic plasticity in the CA1 region of the hippocampus. We show here for the first time that a single injection of the erythropoietin analog darbepoetin alfa reverses pre-existing cognitive deficits in adult rats that had been subjected to transient global ischemia produced by four-vessel occlusion (4-VO). Quantification of neuronal density demonstrated that 12 min of 4-VO selectively killed more than 90% of CA1 neurons in the dorsal hippocampus. Rats that had sustained a bilateral loss of hippocampal CA1 neurons in this range (4-VO rats) displayed more errors and longer escape latencies in the Barnes maze compared with sham-operated controls. A single injection of darbepoetin alfa (5000 U/kg i.p.) 4 h before behavioral testing decreased deficits in escape latency for 4-VO rats but not sham-operated controls. This improvement in spatial working memory performance was correlated with increased levels of nitric-oxide metabolites in the ventral hippocampus. Systemic administration of the nitric-oxide synthase inhibitor N(G)-nitro-l-nitro-arginine methyl ester reversed the increase in nitric-oxide metabolites and improvements in spatial working memory produced by darbepoetin alfa (5000 U/kg, i.p.) at a dose (10 mg/kg, i.p.) that did not impair the spatial working memory performance of intact rats. Taken together, these findings suggest that darbepoetin alfa reverses pre-existing spatial working memory deficits resulting from transient global ischemia by increasing the activity of nitric-oxide synthase, an enzyme implicated in synaptic plasticity.

Footnotes

  • This work was support by a grant from the Heart and Stroke Foundation of Nova Scotia (to G.S.R.). M.L.S. was supported by a studentship from the Nova Scotia Health Research Foundation. K.K. was supported by a Reynolds Postdoctoral Award and a Sobey Postdoctoral Fellowship in Psychiatric Research.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.165530.

  • ABBREVIATIONS:

    4-VO
    four-vessel occlusion
    BSA
    bovine serum albumin
    D alfa
    darbepoetin alfa
    EPO
    erythropoietin
    LTP
    long-term potentiaton
    l-NAME
    N(G)-nitro-l-arginine methyl ester
    NO
    nitric oxide
    NOS
    NO synthase
    NeuN
    neuronal nuclei
    PBS
    phosphate-buffered saline
    ANOVA
    analysis of variance.

    • Received January 4, 2010.
    • Accepted February 17, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleBEHAVIORAL PHARMACOLOGY

Nitric-Oxide Synthase Mediates the Ability of Darbepoetin Alfa to Attenuate Pre-Existing Spatial Working Memory Deficits in Rats Subjected to Transient Global Ischemia

Michel L. Samson, Kosuke Kajitani and George S. Robertson
Journal of Pharmacology and Experimental Therapeutics May 1, 2010, 333 (2) 437-444; DOI: https://doi.org/10.1124/jpet.110.165530

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Research ArticleBEHAVIORAL PHARMACOLOGY

Nitric-Oxide Synthase Mediates the Ability of Darbepoetin Alfa to Attenuate Pre-Existing Spatial Working Memory Deficits in Rats Subjected to Transient Global Ischemia

Michel L. Samson, Kosuke Kajitani and George S. Robertson
Journal of Pharmacology and Experimental Therapeutics May 1, 2010, 333 (2) 437-444; DOI: https://doi.org/10.1124/jpet.110.165530
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