Our recent work suggested that early infusion of nitrite might represent a novel therapeutic approach for acute ischemic stroke. In this study, we sought to examine the therapeutic time window of nitrite in an experimental stroke model, and to develop combined strategies for augmenting its protective effects. Nitrite was infused at various times after ischemia to rats subjected to transient or permanent focal ischemia. Nitrite was infused with memantine to prevent the potential toxicity. Infarct volumes, functional outcomes, microhypoxic areas, and oxidative stress were measured. Nitrite reduced the infarction volume and enhanced functional recovery when administered within 3 and 1.5 h in the transient and permanent model, respectively. Combined therapy with nitrite and memantine prolonged the time window up to 4.5 h. The potential oxidative toxicities of nitrite were significantly inhibited by memantine. The combination therapy of nitrite and memantine may be a feasible therapeutic approach for acute ischemic stroke. (C) 2008 Elsevier Inc. All rights reserved