Curcumin, of which a critical characteristic is the capacity of crossing the blood-brain barrier, has been reported to induce the expression of neuroprotective heme oxygenase (HO)-1. The aim of this study is to compare HO-1-inducing capacity and neuroprotective activity of curcumin, its demethoxy (demethoxycurcumin, DMC; bis-demethoxycurcumin, BDMC) and hydrogenated derivatives (tetrahydrocurcumin, THC) in mouse hippocampal HT22 cells. Curcumin attenuated glutamate-induced cell death through HO-1 expression. DMC lacking a methoxy group on one of the aromatic rings possessed slightly lower activity in HO-1 expression and neuroprotection than curcumin. Similarly, BDMC, which lacks two methoxy groups on both of the aromatic rings, showed less activity than curcumin. These findings suggest that the presence of methoxy groups on the aromatic ring is required to enhance neuroprotective HO-1 expression. The reduction of the diarylheptadienone chain of curcumin by hydrogen, as in THC, was accompanied by a complete loss of ability to induce HO-1 expression and neuroprotection, suggesting that the conjugated double bonds of the central seven-carbon chain of curcumin may be essential for its ability to induce neuroprotective HO-1 expression. Our findings may provide useful information for further development of neuroprotective HO-1 inducers.