We previously reported that 5-methoxyindole-2-carboxylic acid (MICA) could induce preconditioning effect in the ischemic brain of rat. In the present study, we addressed the question of whether MICA could also trigger a postconditioning effect in ischemic stroke. To this end, MICA (100 mg/kg body weight) was injected intraperitoneally at the onset of 24 h reperfusion following 1 h ischemia in rat brain. Results indicate that stroked animals treated with MICA showed less brain infarction volume than that of vehicle-treated animals. Further experiments revealed that brain mitochondrial complexes I and IV showed elevated enzymatic activities in MICA treated group and the elevation in complex I activity was likely contributed by seemingly enhanced expression of many complex I subunits, which was determined by mass spectral peptide sequencing. When compared with vehicle-treated rats, the preservation of complexes I and IV activities was shown to be accompanied by enhanced mitochondrial membrane potential, increased ATP production, and decreased caspase-3 activity. Additional studies also indicate the involvement of NQO1 upregulation by the Nrf2 signaling pathway in this MICA postconditioning paradigm. Consequently, attenuated oxidative stress in the MICA treated group reflected by decrease in H2O2 production and protein carbonylation and lipid peroxidation was detected. Taken together, the present study demonstrates that MICA can also induce a postconditioning effect in the ischemic brain of rat and the underlying mechanism likely involves preservation of mitochondrial function, upregulation of cellular antioxidative capacity, and attenuation of oxidative stress. (C) 2018 Elsevier Inc. All rights reserved.