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
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|