PT  - JOURNAL ARTICLE
AU  - George S. Robertson
AU  - Kosuke Kajitani
AU  - Michel Samson
TI  - Nitric Oxide Synthase Mediates the Ability of Darbepoetin alfa to Attenuate Pre-existing Spatial Working Memory Deficits in Rats Subjected to Transient Global Ischemia
AID  - 10.1124/jpet.110.165530
DP  - 2010 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.110.165530
4099  - http://jpet.aspetjournals.org/content/early/2010/02/18/jpet.110.165530.short
4100  - http://jpet.aspetjournals.org/content/early/2010/02/18/jpet.110.165530.full
AB  - Erythropoietin has been reported to improve the behavioral performance of healthy mice in tests thought to be dependent upon synaptic plasticity in the CA1 region of the hippocampus. We show here for the first time that a single injection of the erythropoietin analogue, darbepoetin alfa, reverses pre-existing cognitive deficits in adult rats that had been subjected to transient global ischemia produced by 4-vessel occlusion (4-VO). Quantification of neuronal density demonstrated that 12 minutes of 4-VO selectively killed greater 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 to sham-operated controls. A single injection of darbepoetin alfa (5000 U/kg, i.p.) 4 hours 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, L-NAME, 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.The American Society for Pharmacology and Experimental Therapeutics