Abstract: Objective To study the effect of ibuprofen on acid-sensitive ion channels in rat's cortical ischemic penumbra and investigate its protective effect on cerebral ischemia-reperfusion injury and its mechanism. Methods Forty-eight healthy male adult SD rats were randomly divided into 4 groups: sham operation + vehicle group (S + R), sham operation + ibuprofen group (S + B), model + vehicle group (C + R), model + ibuprofen group (C + B) with 12 in each group. Sham operation group only received separating blood vessels without embolization. Middle cerebral artery occlusion (MCAO) was used to establish the modal. Ibuprofen (240 mg/kg·day) was delivered with 80 mg/kg intraperitoneally at 1 h before MCAO and every 8 hours thereafter, for a total of three injections in the ibuprofen group. Rats in the vehicle group were injected intraperitoneally with equivolumetric arginine vehicle. The neuroprotective effect of ibuprofen was evaluated at 24 h after MCAO by neurobehavioral score and TTC staining. The effect of ibuprofen on the expressions of ASIC1a and ASIC2a protein in cortical ischemic penumbra was assessed by western blot. Results Compared with S + R group (17.56±0.15), the neurological score of C + R group (6.06±0.35) decreased significantly (P＜ 0.05). Compared with C + R group, the neurological score of C + B group (11.94±0.33) increased (P＜ 0.05), and the percentage of cerebral infarction volume decreased significantly (C+B 11.24%±0.93% vs C+R 20.03%±1.74%, P＜ 0.01). There was no significantdifference in the relative expression level of ASIC1a (0.99±0.07) in the cortical ischemic penumbra of C + R group compared with S + R group (1.00±0.04) (P=0.12), while the content of ASIC1a membrane protein (1.40±0.11 vs 0.96±0.04, P＜ 0.05) and the expression level of ASIC2a (1.87±0.14 vs 0.98±0.07, P＜ 0.01) significantly increased. Compared with C + R group, the expression level of ASIC1a was down-regulated, but the difference was not statistically significant (0.79±0.08 vs 0.99±0.07, P=0.07). The content of ASIC1a membrane protein (1.40±0.11 vs 0.98±0.12) and the expression of ASIC2a in C+B group (1.87±0.14 vs 1.18±0.12) were significantly lower than those in C + R group (P＜ 0.05, respectively). Conclusion Ibuprofen has neuroprotective effect, which may be achieved by inhibiting the up-regulation of ASIC2a and reducing the protein content of ASIC1a.