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Synergistic protective effects of erythropoietin and olmesartan on ischemic stroke survival and post-stroke memory dysfunctions in the gerbil

Faure, Sebastiena; Oudart, Nicolea; Javellaud, Jamesa; Fournier, Albertb; Warnock, David Gc; Achard, Jean-Michela

doi: 10.1097/01.hjh.0000249704.34607.4c
Original papers: Stroke
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Objectives 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.

Conclusion 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.

aDivision of Nephrology & Department of Pharmacology and Physiology, University of Limoges, France

bDivision of Nephrology University of Amiens, France

cDivision of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA

Received 10 March, 2006

Revised 10 June, 2006

Accepted 6 July, 2006

Correspondence and requests for reprints to Prof. Jean-Michel Achard, MD, PhD, Department of Physiology, Faculté de Médecine, 2 rue du Dr Marcland, 87000 Limoges, France Tel: +33 555 43 58 75; fax: +33 555 43 58 77; e-mail: jean-michel.achard@unilim.fr

Sponsorship: This work was supported by grants from the Fondation pour la Recherche Médicale, the Société Française d'Hypertension Artérielle, the Club des Jeunes Hypertensiologues. S.F. was supported by the Conseil Régional Limousin.

Part of this work has been published in abstract form (Hypertension 2005; 46:813).

© 2006 Lippincott Williams & Wilkins, Inc.