Lysophosphatidic Acid Induces Necrosis and Apoptosis in Hippocampal Neurons

Abstract

A diverse body of evidence indicates a role for the lipid biomediator lysophosphatidic acid (LPA) in the CNS. This study identifies and characterizes the induction of neuronal death by LPA. Treatment of cultured hippocampal neurons from embryonic rat brains with 50~eM LPA resulted in neuronal necrosis, as determined morphologically and by the release of lactate dehydrogenase. A concentration of LPA as low as 10~iMled to the release of lactate dehydrogenase. In contrast, treatment of neurons with 0.1 or 1.0 j.tM LPA resulted in apoptosis, as determined by chromatin condensation. In addition, neuronal death induced by 1 ,aM LPA was characterized as apoptotic on the basis of terminal dUTP nick end-labeling (TUNEL) staining, externalization of phosphatidylserme, and protection against chromatin condensation, TU N EL staining, and phosphatidylserine externalization by treatment with N-benzyloxycarbonyl-Val-Ala-Aspfluoromethyl ketone, a broad-spectrum inhibitor of caspases, i.e., members of the interleukin-1/3 converting enzyme family. Studies with antagonists of ionotropic glutamate receptors did not indicate a significant role for these receptors in apoptosis induced by 1 1iM LPA. LPA (1 1iM) also induced a decrease in mitochondrial membrane potential. Moreover, pretreatment of neurons with cyclosporin A protected against the LPA-induced decrease in mitochondrial membrane potential and neuronal apoptosis. Thus, LPA, at pathophysiological levels, can induce neuronal apoptosis and could thereby participate in neurodegenerative disorders. Key Words: Lysophosphatidic acid-Apoptosis-Neurons-Mitochondrial membrane potential -Cyclosporin A.

Rho/ROCK pathway is essential to the expansion, differentiation, and morphological rearrangements of human neural stem/progenitor cells induced by lysophosphatidic acid

“…We found that LPA promoted apoptosis of early human NS/PCs, as revealed by neurosphere formation assay, which is consistent with some NS/PC and neuroblast studies performed in rodents ( 16,17,38,57,58 ) but differs with others in which LPA improves cell survival ( 16,38 ) or proliferation ( 13,35,59 ). In human cells, we previously showed that LPA does not modify apoptosis of older hESCderived NS/PCs ( 39 ) as, when two-week-old hESC-derived within minutes; Fig.…”

Lysophosphatidic Acid Inhibits Neuronal Differentiation of Neural Stem/Progenitor Cells Derived from Human Embryonic Stem Cells

“…During such events, which damage the blood-brain barrier, levels of LPA within the nervous system are hypothesized to increase to 10 M (reviewed in [33,34]). LPA has been shown to stimulate astrocytic proliferation [7,34], and depending on its concentration, it has also been described as promoting death of hippocampal neurons, by apoptosis (1 M) or by necrosis (10 M) [35]. Moreover, LPA has recently been described as cytotoxic to the neuromicrovascular endothelium [36].…”

Regulation of Stem Cell Pluripotency and Neural Differentiation by Lysophospholipids

“…LPA injections into mouse brain induce astrocyte reactivity at the site of the injury [115] , while in the spinal cord following trauma, LPA induces neuropathic pain and demyelination [116][117][118][119][120][121] . LPA can stimulate astrocytic proliferation [87,111] and, depending on its concentration, it can promote death of hippocampal neurons by apoptosis (1 M ) or by necrosis (10 M ) [122] . Moreover, LPA mediates microglial activation [81] and is cytotoxic to the neuromicrovascular endothelium [123] .…”