4-hydroxynonenal (4-HNE) is a major aldehyde produced during the lipid peroxidation of omega-6 polyunsaturated fatty acids. Recently, 4-HNE has been reported to contribute to the pathogenesis of neuronal diseases such as Alzheimer's disease. However, the role of 4-HNE in ischemic stroke is unclear yet. In this study, we found that plasma 4-HNE concentrations were higher in the genetic stroke-prone rats (stroke-prone spontaneously hypertensive rats) and experimental stroke rats with middle cerebral artery occlusion (MCAO). Moreover, administration of 4-HNE via intravenous injection before MCAO surgery not only enlarged cerebral ischemia-induced infarct area, but also increased oxidative stress in brain tissue, which was evidenced by the enhanced ROS/MPA levels, and the reduced GSH/GSSG ratio and MnSOD levels. Overexpression of aldehyde dehydrogenasesbcl-2 (ALDH2), an enzyme catalyses 4-HNE, rescued neuronal survival against 4-HNE treatment in PC12 cells. The plasma 4-HNE concentrations in patients with ischemic stroke were higher than those in control subjects. In a small sample population (N = 60), the plasma 4-HNE concentration was positively correlated with the plasma homocysteine concentration, a risk factor for ischemic stroke. Taken together, our study suggests that the plasma 4-HNE level is a potential biomarker for ischemic stroke. (C) 2012 Elsevier Inc. All rights reserved.