Lysophosphatidylcholine protects cerebellar granule neurons from apoptotic cell death

Abstract

Cultured cerebellar granule neurons (CGNs) undergo apoptosis when deprived of depolarizing stimulation and provide an in vitro model system with which to study the effects of neurotrophic substances. Our previous results showed that secretory phospholipases A(2) (sPLA(2)s) protect CGNs from apoptotic cell death under the nondepolarizing condition. In this study, we further analyzed the mechanism whereby sPLA(2) exhibits this effect. Among the primary metabolites of sPLA(2) tested, lysophosphatidylcholine (LPC), but not other lysophospholipids, remarkably rescued CGNs from apoptosis. In contrast, neither arachidonic nor oleic acids displayed neurotrophic effect. Release of LPC into the culture media occurred in response to sPLA(2) treatment, and degradation or sequestration of LPC attenuated the survival-promoting effects of sPLA(2) and LPC. The neurotrophic effect of LPC required the presence of extracellular Ca(2+) and L-type Ca(2+) channel activity, suggesting that Ca(2+) influx across the plasma membrane is evoked by LPC. sPLA(2)- or LPC-induced promotion of CGN survival was suppressed by inhibitors of protein kinase A and phospholipase C, suggesting that they play a role in mediating survival-promoting signal of sPLA(2). The results presented here demonstrate a novel, unexpected neurotrophin-like effect of LPC in the central nervous system.

Lysophosphatidylcholine enhances NGF‐induced MAPK and Akt signals through the extracellular domain of TrkA in PC12 cells

“…Interestingly, similar headgroup specificity of these lysophospholipids was observed in our previous studies wherein neurite outgrowth in PC12 cells and the cell survival of CGNs were examined; only LPC, but not other lysophospholipids, induced neurites in PC12 and rescued CGNs from apoptosis [20,21]. Furthermore, LPC with fatty acyl chains of C14:0, C16:0, C18:0, and C18:1, but not C12:0, enhanced NGF‐induced MAPK phosphorylation in this study, and similar LPC species were effective on neurite outgrowth in PC12 cells and the cell survival of CGNs in our previous studies [20,21]. These results suggest the existence of specific and acyl chain‐dependent role(s) of LPC in neuronal systems.…”

“…We previously demonstrated that sPLA 2 displays neurotrophin‐like activities, such as neurite‐induction in PC12 cells and rescue of CGNs from apoptosis. These effects of sPLA 2 were essentially attributable to the generation of LPC [20,21]. Here we tested if exogenously‐added sPLA 2 also enhances NGF‐induced MAPK phosphorylation.…”

“…Subsequent studies have shown that the neurotrophin‐like activity of sPLA 2 is associated with the release of lysophosphatidylcholine (LPC). Indeed, LPC added to PC12 and CGNs cultures recapitulated the neurotrophin‐like activities of sPLA 2 [20,21].…”

Partial characterization of proapoptotic action of biliary deteriorated lipids on biliary epithelial cells in pancreaticobiliary diseases

“…In addition, previous in vitro studies have demonstrated proapoptotic effect of LPC in human endothelial cells, hippocampal progenitor cells, and pancreatic exocrine cells . In contrast, exogenous treatment of LPC reduced low potassium‐induced apoptosis in cerebellar granule neurons in vitro . Taken together, LPC might play distinct roles specifically to tissues or cells.…”

Lysophosphatidylcholine Potentiates BDNF-Induced TrkB Phosphorylation and Downstream Signals in Cerebellar Granule Neurons

“…9,10) We have reported that LPC significantly enhanced NGFinduced MAPK and Akt phosphorylation by stimulating the activation of TrkA in PC12 and CHO-K1 cells through the extracellular domain of TrkA. 11) In the present study, we aimed to determine whether LPC has a similar effect on the BDNF-TrkB pathway.…”