Transient global cerebral ischemia. one of the consequences of cardiac arrest and cardiovascular surgery. usually leads to delayed death of hippocampal cornu Ammonis1 (CA1) neurons and cognitive defi cits. Currently. there are no effective preventions or treatments for this condition. Omega-3 (-3) PUFAs have been shown to have therapeutic potential in a variety of neurological disorders. Here, we report that the transgenic mice that express the fat-1 gene encoding for -3 fatty acid desaturase, which leads to an increase in endogenous = -3 PUFAs and a concomitant decrease in = -6 PUFAs, were protected from global cerebral ischemia injury. The results of the study show that the hippocampal CA1 neuronal loss and cognitive defi cits induced by global ischemia insult were signifi cantly less severe in fat-1 mice than in WT mice controls. The protection against global cerebral ischemia injury was closely correlated with increased production of resolvin D1, suppressed nuclear factor-kappa B activation, and reduced generation of pro-infl ammatory mediators in the hippocampus of fat-1 mice compared with WT mice controls. Our study demonstrates that fat-1 mice with high endogenous = -3 PUFAs exhibit protective effects on hippocampal CA1 neurons and cognitive functions in a global ischemia injury model. -Luo, C., H. Ren, J-B. Wan, X. Yao, X. Zhang, C. He, K-F. So, J. X. Kang, Z. Pei, and H. Su. Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury. J. Lipid Res . 2014 . 55: 1288-1297. © 2014 by the American Society for Biochemistry and Molecular Biology.