Abstract: OBJECTIVE To investigate the neuroprotective effects of progesterone(PROG) on cerebral in rats with ischemia-reperfusion(I/R) brain injury and its possible molecular mechanism. METHODS One hundred and thirty-eight rats were randomly divided into Sham group, middle cerebral artery occlusion(MCAO) group and PROG+MCAO group. Motor function and cognitive function of rats was evaluated by Longa method and Morris water maze test. TTC staining, magnetic resonance spectroscopy(MRS) and Annexin V-FITC/PI double staining were used to evaluate nerve cell injury. The levels of ATP, IL-6, TNF-α and COX-2 in rat cerebrospinal fluid was determined by ELISA. The expression of P2X₇ receptor(P2X₇R) and NF-κB protein in brain tissue was detected by Western blotting. RESULTS Compared with the MCAO group, the Longa score(Day 5-7) and the latency of Morris water maze test(Day 4-7) in the PROG+MCAO group decreased(P<0.05 or P<0.01), while the number of target crossovers increased(P<0.05). The ratio of NAA/Cr and Cho/Cr in the PROG+MCAO group was higher than that in the MCAO group, and the cerebral infarction volume and apoptosis rate were all significantly lower than that in the MCAO group(P<0.05). The levels of ATP, COX-2, TNF-α and IL-6 in the cerebrospinal fluid of MCAO group were significantly higher than those in sham group, and the PROG+MCAO group were significantly lower than MCAO group(P<0.05). The expression level of P2X₇ receptor and NF-κB in MCAO group were higher than that of the Sham group, while the PROG+MCAO group was significantly lower than that of the MCAO group(P<0.05). CONCLUSION PROG improves motor and cognitive function in rats with I/R brain injury by reducing neuronal apoptosis rate and alleviating neuronal damage and myelin degradation. This protective effect is closely related to its inhibition of ATP-P2X₇R signaling pathway.