Lysophosphatidic acid induces necrosis and apoptosis in hippocampal neurons

Frederick W. Holtsberg, Marion R. Steiner, Jeffrey N. Keller, Robert J. Mark, Mark P. Mattson, Sheldon M. Steiner

Research output: Contribution to journalArticlepeer-review

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 μM LPA resulted in neuronal necrosis, as determined morphologically and by the release of lactate dehydrogenase. A concentration of LPA as low as 10 μM led to the release of lactate dehydrogenase. In contrast, treatment of neurons with 0.1 or 1.0 μM LPA resulted in apoptosis, as determined by chromatin condensation. In addition, neuronal death induced by 1 μM LPA was characterized as apoptotic on the basis of terminal dUTP nick end-labeling (TUNEL) staining, externalization of phosphatidylserine, and protection against chromatin condensation, TUNEL staining, and phosphatidylserine externalization by treatment with N-benzyloxycarbonyl-Val-Ala-Asp- fluoromethyl ketone, a broad-spectrum inhibitor of caspases, i.e., members of the interleukin-1β converting enzyme family. Studies with antagonists of ionotropic glutamate receptors did not indicate a significant role for these receptors in apoptosis induced by 1 μM LPA. LPA (1 μM) 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.

Original languageEnglish (US)
Pages (from-to)66-76
Number of pages11
JournalJournal of Neurochemistry
Volume70
Issue number1
StatePublished - Jan 1998
Externally publishedYes

Keywords

  • Apoptosis
  • Cyclosporin A
  • Lysophosphatidic acid
  • Mitochondrial membrane potential
  • Neurons

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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