Evidence for an active type of cell death with ultrastructural features distinct from apoptosis: The effects of 3-acetylpyridine neurotoxicity
3-Acetylpyridine is a niacinamide antagonist with potent neurotoxic properties in vitro and in vivo. 3-Acetylpyridine neurotoxicity was associated with positive DNA end-labelling and displayed features of active cell death without the ultrastructural changes of apoptotic cell death. After systemic a...
Saved in:
Published in | Neuroscience Vol. 81; no. 3; pp. 721 - 734 |
---|---|
Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Oxford
Elsevier Ltd
01.12.1997
Elsevier |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 3-Acetylpyridine is a niacinamide antagonist with potent neurotoxic properties
in vitro and
in vivo. 3-Acetylpyridine neurotoxicity was associated with positive DNA end-labelling and displayed features of active cell death without the ultrastructural changes of apoptotic cell death. After systemic administration in rats (70
mg/kg), we detected labelled nuclei in the inferior olive using
in situ DNA end-labelling. However, the conventional chromatin stain did not show chromatin condensation or fragmentation and electron microscopy studies failed to reveal features of apoptosis. Although areas of condensed chromatin were present in some nuclei, cytoplasmic damage with extensive organelle swelling was the most prominent finding.
In vitro, 3-acetylpyridine (0.1–1
mM) induced degeneration of cerebellar granule neurons in a concentration- and time-dependent manner. The protein synthesis inhibitor cycloheximide (10
μg/ml) and the transcriptional inhibitor actinomycin D (10
μM) protected against 3-acetylpyridine toxicity. In contrast, neither the free radical scavenger
α-phenyl-N-tertbutylnitron (100
μM), nor glutathione ethyl ester (10–100
μM), N-acetyl-cysteine (10–200
μM) or 3-aminobenzamide (0.1–4
mM), an inhibitor of poly(ADP-ribose) synthesis, were effective. 3-Acetylpyridine-induced neuronal death
in vitro was associated with positive
in situ DNA labelling. However, DNA fragmentation could not be demonstrated prior to neuronal cell loss and no DNA “laddering” was detected by DNA gel electrophoresis. Correspondingly, no apoptotic nuclei were revealed upon electron microscopy but organelle swelling and extensive vacuolization, changes similar to autophagocytosis.
In conclusion, 3-acetylpyridine induces an active form of cell death that required
de novo protein synthesis but is distinct from apoptosis. A loss of glutathione accompanies, but does not precede, cell death. |
---|---|
Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0306-4522 1873-7544 |
DOI: | 10.1016/S0306-4522(97)00181-4 |