4-Methylcatechol (4MC), a stimulator of the synthesis of neurotrophin family members in various cells, was able to up-regulate the expression of heme oxygenase (HO)-1, a redox-sensitive inducible stress protein, in neural stem/progenitor cells (NS/PCs). RT-PCR analysis showed that 4MC induced HO-1 mRNA expression in a dose- and a time-dependent manner. The increase in HO-1 mRNA was followed by an increase in HO-1 protein content, which was confirmed by ELISA and Western blotting analysis. When NS/PCs were pretreated with 4MC before exposure to hydrogen peroxide (H(2)O(2)), most of the cells were rescued from the H(2)O(2)-induced death. 4MC enhanced the phosphorylation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) and Akt in a time-dependent manner. Pretreatment of cultures with a selective inhibitor of PI3 kinase (PI3K)/Akt, but not with one of MAPK/ERK, inhibited both the 4MCinduced HO-1 expression and neuroprotective effect, demonstrating that PI3K/Akt signaling pathway played a significant role in 4MC-induced HO-1 induction and neuroprotection. Taken together, our results suggest that 4MC activates the expression of HO-1 through the PI3K/Akt signaling pathway and that the HO-1 protein inhibits the death of NS/PCs induced by oxidative stress.