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Lysophosphatidic Acid Induces Necrosis and Apoptosis in Hippocampal Neurons
Author(s) -
Holtsberg Frederick W.,
Steiner Marion R.,
Keller Jeffrey N.,
Mark Robert J.,
Mattson Mark P.,
Steiner Sheldon M.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.70010066.x
Subject(s) - lysophosphatidic acid , tunel assay , biology , apoptosis , phosphatidylserine , microbiology and biotechnology , programmed cell death , receptor , biochemistry , phospholipid , membrane
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 µ M LPA resulted in neuronal necrosis, as determined morphologically and by the release of lactate dehydrogenase. A concentration of LPA as low as 10 µ M led to the release of lactate dehydrogenase. In contrast, treatment of neurons with 0.1 or 1.0 µ M LPA resulted in apoptosis, as determined by chromatin condensation. In addition, neuronal death induced by 1 µ M 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 µ M LPA. LPA (1 µ M ) 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.