The fate of cells under anoxic or ischemic stress is determined by intracellular signaling pathways including the mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K/Akt), which affect downstream members of the apoptotic cascade. The freshwater turtle Trachemys scripta is extremely tolerant of anoxia, surviving up to 48 h at room temperature and for weeks at 3 degrees C in the complete absence of oxygen. We investigated the relationship between the neuroprotective purine adenosine, which increases greatly in the anoxic turtle brain, and MAPK and Akt activation during both short (1 h) and long-term (4 h) anoxia. ERK1/2 and Akt were significantly upregulated during the first hour of transition to full anoxia, but returned to baseline by 4 h anoxia. Conversely, p38MAPK levels were suppressed by a mean 71% at 1 h anoxia but also returned to baseline by 4 h anoxia. Systemic administration of the general adenosine receptor antagonist aminophylline abrogated the increases in both phosphorylated ERK1/2 and Akt, as well as the initial suppression of p38MAPK. The differential modulation of the MAPK/Akt pathways may be critical for neuronal protection during the initial transition to the hypometabolic state during anoxia, when physiologic stress is likely to be greatest.