Troglitazone (TGZ), an antidiabetic drug that improves insulin-resistance in the peripheral tissues, was tested for neurotrophic activity in motoneurones and other neurones in culture. In rat motoneurones, TGZ had a remarkable effect on survival, which was comparable or superior to that of brain-derived neurotrophic factor, a known potent neurotrophic factor for rat motoneurones. However, TGZ did not promote the survival of sensory, sympathetic, septal or hippocampal neurones. The effect of TGZ on motoneurones was additive to that of insulin-like growth factor-I and both activities were inhibited by phosphatidylinositol 3-kinase (PI3-kinase) inhibitors, wortmannin and LY294002, suggesting the involvement of the activation of PI3-kinase in the activity of TGZ. Pioglitazone, another antidiabetic drug structurally similar to TGZ, did not show any activity, indicating that the agonistic activity of TGZ for peroxisome proliferator-activated receptor-gamma is not involved in the survival activity. Chromanol, an antioxidant moiety of TGZ, showed little or no survival activity. These results indicate specific neurotrophic activity of TGZ for motoneurones through the activation of PI3-kinase and support the applicability of TGZ for the treatment of motor neurone diseases such as amyotrophic lateral sclerosis.