LYSOPHOSPHATIDIC ACID AND APOPTOSIS OF NERVE GROWTH FACTOR-DIFFERENTIATED PC12 CELLS

The lipid biomediator lysophosphatidic acid (LPA) elicits a unique res ponse in hippocampal neurons, LPA induces neuronal apoptosis, This stu dy explores the effects of LPA on cells with neuronal properties, nerv e growth factor-differentiated PC6 cells, a clone of PC12 cells, LPA i nduced apoptosis in these cells as assessed by chromatin condensation, terminal dUTP nick end-labeling of DNA, protection against these nucl ear alterations by a general caspase inhibitor and the lack of release of lactic dehydrogenase, LPA caused oxidative stress, namely a decrea sed reduction of MTT, -(4,5-dimethylthiazol-2-yl)-2,5-diphenytetrazoli um bromide. This oxidative stress appears to be of functional signific ance, since cells were protected by pretreatment with the antioxidant propyl gallate and by stable transfection with cDNA encoding the antio xidant enzyme, manganese superoxide dismutase, Mitochondrial and nitri c oxide participation in LPA-induced apoptosis are suggested by the pr otection afforded by pretreatment with either cyclosporin A, an inhibi tor of mitochondrial permeability transition, or nitric oxide synthase inhibitors. The nitric oxide synthase inhibitor findings are novel, s ince to our knowledge, LPA has not heretofore been associated with an increase in nitric oxide. In addition, as observed for many neurotoxic agents, insulin-like growth factor I protected against LPA-induced ap optosis of PC6 cells. (C) 1998 Wiley-Liss, Inc.