Synergistic protective effects of erythropoietin and olmesartan on ischemic stroke survival and post-stroke memory dysfunctions in the gerbil.
OBJECTIVE
Treatment with erythropoietin and AT1 blockers is protective in experimental acute cerebral ischemia, with promising results in pilot clinical studies in human stroke. This paper examines the effects of using both agents as combination therapy in acute ischemic stroke.


METHODS
We used the single carotid ligation stroke model in the gerbil. Six groups of 50 gerbils were treated either with placebo, erythropoietin (intraperitoneally, 5000 IU/kg, 2 and 48 h after stroke), olmesartan (10 mg/kg per day in drinking water started 36 h after stroke), ramipril (2.5 mg/kg per day in drinking water started 36 h after stroke), erythropoietin + olmesartan, or erythropoietin + ramipril. Long-term (1 month) Kaplan-Meyer survival curves were obtained, and survivors were submitted at day 30 to immediate (object recognition test) and spatial (Morris water maze) memory function tests.


RESULTS
Erythropoietin alone and olmesartan alone, but not ramipril, significantly increased survival at day 30 compared with untreated controls (38, 30 and 6% versus 12%, respectively). Combined treatment with erythropoietin and olmesartan further increased the survival rate to 56%, whereas combined therapy with erythropoietin and ramipril decreased 30-day survival to 24% (P < 0.0001, erythropoietin + olmesartan versus erythropoietin + ramipril). Untreated stroke survivors had markedly altered performances in both the object recognition test (P = 0.0007) and the Morris water maze (P < 0.0001) tests at day 30 compared with normal gerbils. In erythropoietin-treated animals, ramipril therapy had no beneficial effect whereas olmesartan fully restored normal response to the memory tests.


CONCLUSIONS
Post-infarct treatment with olmesartan combined with early erythropoietin therapy has a protective effect on survival, and markedly improves long-term memory dysfunction in this experimental model.
Faure
Sebastien
S
Division of Nephrology & Department of Pharmacology and Physiology, University of Limoges, France.
Oudart
Nicole
N
Javellaud
James
J
Fournier
Albert
A
Warnock
David G
DG
Achard
Jean-Michel
JM
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000494:pharmacology*; D005849:Gerbillinae; D007093:Imidazoles / Q000494:pharmacology*; D053208:Kaplan-Meier Estimate; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017257:Ramipril / Q000494:pharmacology*; D011994:Recombinant Proteins; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D013777:Tetrazoles; D004921:Erythropoietin; C437965:olmesartan; D017257:Ramipril