Lysophosphatidic acid and apoptosis of nerve growth factor-differentiated PC12 cells

Abstract

The lipid biomediator lysophosphatidic acid (LPA) elicits a unique response in hippocampal neurons, LPA induces neuronal apoptosis. This study explores the effects of LPA on cells with neuronal properties, nerve growth factor-differentiated PC6 cells, a clone of PC12 cells. LPA induced apoptosis in these cells as assessed by chromatin condensation, terminal dUTP nick end-labeling of DNA, protection against these nuclear alterations by a general caspase inhibitor and the lack of release of lactic dehydrogenase. LPA caused oxidative stress, namely a decreased reduction of MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. This oxidative stress appears to be of functional significance, since cells were protected by pretreatment with the antioxidant propyl gallate and by stable transfection with cDNA encoding the antioxidant enzyme, manganese superoxide dismutase. Mitochondrial and nitric oxide participation in LPA-induced apoptosis are suggested by the protection afforded by pretreatment with either cyclosporin A, an inhibitor of mitochondrial permeability transition, or nitric oxide synthase inhibitors. The nitric oxide synthase inhibitor findings are novel, since 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 apoptosis of PC6 cells.

Lysophosphatidic acid induces endothelial cell death by modulating the redox environment

“…For instance, toxic effects of LPA have been reported in T cells and neurons, and the latter have been proposed to play a role in brain injury (26,27,41,60). As demonstrated in the current study, LPA also may partake in brain injury by causing endothelial cell demise and microvascular degeneration.…”

Effects of lysophosphatidic acid and its receptors LPA__AMB__frac13; on radiation pneumonitis

“…First, irradiation-induced oxidative damage is the initial pathogenic event in RP, and decreased oxidative stress using extracellular superoxide dismutase can protect normal lung tissue from radiation injury (21). LPA can cause oxidative stress in nerve growth factor-differentiated PC12 cells, thus leading to apoptosis of these cells (22). In our study, irradiation-induced oxidative stress, which was assayed by biochemical measurement of MDA levels, was reduced after VPC-12249 administration, which may result in a protective effect against RP.…”

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…Interestingly, studies have also found evidence of concentration-dependent LPA-mediated necrosis as well as apoptosis, possibly through oxidative stress (103)(104)(105). In vitro experiments have demonstrated the effects of LPA 1 -mediated stimulation that increase the proliferation and differentiation on primary neuroprogenitor cell (NPC) cultures, neuronal cell lines, and primary neurons (90,106,107).…”