Previous studies have shown that xenon-delayed postconditioning for up to 2 h after reperfusion provides protection against spinal cord ischemia/reperfusion (I/R) injury in rats. This study was designed to determine the roles of phosphatidylinositol 3-kinase (PI3K)-Akt and extracellular signal-regulated kinase (ERK) in this neuro-protection. The rats were randomly assigned to the following nine groups (n = 16 * 9): 1) I/R + N-2 group, 2) I/R + Xe group, 3) I/R + PD98059 + N-2 group (ERK blocking agent), 4) I/R + wortmannin + N-2 group (PI3K-Akt blocking agent), 5) I/R + PD98059 + Xe group, 6) I/R + wortmannin + Xe group, 7) I/R + DMSO + Xe group (di-methyl sulfoxide, vehicle control), 8) I/R + DMSO + N-2 group, and 9) sham group (no spinal cord ischemia and no xenon). Spinal cord ischemia was induced for 25 min in male Sprague-Dawley rats. Neurological function was assessed using the Basso, Beattie, and Bresnahan (BBB) open-field locomotor scale at 6, 12, 24 and 48 h after reperfusion. Histological examination of the lumbar spinal cord was performed using Nissl staining and TUNEL staining at 4 (n = 8) and 48 (n = 8) h after reperfusion. Western blotting was performed to evaluate p-Akt and p-ERK expression in the spinal cord at 4 (n = 8) and 48 (n = 8) 11 after reperfusion. Compared with the sham group, all rats in the I/R groups had lower BBB scores, fewer normal motor neurons, more apoptotic neurons and lower p-Akt and p-ERK levels at each time point (P < 0.05). Compared with the I/R group, rats in the I/R+ Xe group had higher neurological scores, more normal motor neurons, fewer apoptotic neurons and significantly higher levels of p-Akt and p-ERK at each time point (P < 0.05). Compared with the I/R+ Xe group, the I/R+ PD98059 + Xe and I/R + wortmannin + Xe groups showed worse neurological outcomes and less p-Akt and p-ERK at each time point (P < 0.05). These results suggest that xenon-delayed postconditioning improves neurological outcomes to spinal cord I/R injury in rats through the activation of the AKT and ERK signaling pathways. (C) 2016 Elsevier B.V. All rights reserved.