Interaction of various intracellular signaling mechanisms involved in mononuclear phagocyte toxicity toward neuronal cells

Microglia become activated in a wide range of neurodegenerative disorders, including Alzheimer's disease. Such activation may lead to autodestruction of neurons. It is demonstrated here that activation of both human microglia and monocytic THP-1 cells by a combination of lipopolysaccharide and inter feron-gamma results in secretion of neurotoxins that kill human neuronal SH -SY5Y cells. This neurotoxicity can be partially blocked by inhibitors of c ytosolic phospholipase A(2), cGMP-selective phosphodiesterases, or protein kinase C, When combinations of these inhibitors, or combinations of an inhi bitor plus nordihydroguaiaretic acid, or the nonsteroidal anti-inflammatory drug diclofenac were tried, additive reductions in neurotoxicity were obse rved. It is concluded that the stimulants activated multiple intracellular pathways, and that combination therapies inhibiting these pathways might be beneficial for treating neurodegenerative disorders.