Survival activity of troglitazone in rat motoneurones

Troglitazone (TGZ), an antidiabetic drug that improves insulin-resistance i n the peripheral tissues, was tested for neurotrophic activity in motoneuro nes and other neurones in culture. In rat motoneurones, TGZ had a remarkabl e effect on survival, which was comparable or superior to that of brain-der ived neurotrophic factor, a known potent neurotrophic factor for rat motone urones. However, TGZ did not promote the survival of sensory, sympathetic, septal or hippocampal neurones. The effect of TGZ on motoneurones was addit ive to that of insulinlike growth factor-I and both activities were inhibit ed by phosphatidylinositol 3-kinase (PI3-kinase) inhibitors, wortmannin and LY294002, suggesting the involvement of the activation of PI3-kinase in th e activity of TGZ. Pioglitazone, another antidiabetic drug structurally sim ilar to TGZ, did not show any activity, indicating that the agonistic activ ity of TGZ for peroxisome proliferator-activated receptor-gamma is not invo lved in the survival activity. Chromanol, an antioxidant moiety of TGZ, sho wed little or no survival activity. These results indicate specific neurotr ophic activity of TGZ for motoneurones through the activation of PI3-kinase and support the applicability of TGZ for the treatment of motor neurone di seases such as amyotrophic lateral sclerosis.