Diallyl disulfide (DADS) is one of the organosulfur compounds of garlic. The effects of DADS on neuronal cells have not clearly been established. We investigated its effects on the viability of neuronal cells (N18D3 cells), the levels of free radical and membrane lipid peroxidation, and the cell signals, such as phosphatidylinositol 3-kinase (PI3K)/Akt and glycogen synthase kinase-3 (GSK-3). When N18D3 cells were treated with several concentrations of DADS, the viability was not affected up to 25 microM, however, decreased at higher than 25 microM. The levels of free radicals and membrane lipid peroxidation were increased in a dose-dependent manner, especially at higher than 25 microM. The treatment of N18D3 cells with 25 microM DADS slightly increased the expressions of p85a PI3K, phosphorylated Akt and phosphorylated GSK-3, but the treatment with 100 microM significantly reduced them. To evaluate whether low concentration of DADS, up to 25 microM, had protective effect on oxidative stress-injured N18D3 cells, the viability of N18D3 cells (pretreated with DADS for 2h versus not pretreated) was evaluated 24h after their exposure to 100 microM H(2)O(2) for 30 min. Compared to the cells treated with only 100 microM H(2)O(2), the pretreatment with 25 microM DADS increased the viability, and the expressions of p85a PI3K, phosphorylated Akt and phosphorylated GSK-3. These results indicate that low concentration of DADS has protective effects on N18D3 cells, whereas high concentration is rather cytotoxic. Therefore, some specific optimum concentration of DADS may be a new potential therapeutic strategy for oxidative stress-injury in vitro model of neurodegenerative diseases.