Glucocorticoid endangerment of hippocampal neurons does not involve deoxyribonucleic acid cleavage.
Glucocorticoids (GCs) are highly pathogenic if secreted in excess. Recent work shows that such deleterious consequences include damage to the hippocampus, a principal neural target site for GCs. Excessive chronic exposure to GCs accelerates senescent hippocampal neuron loss, while the presence of GCs at the time of neurological insults, such as seizure or hypoxia-ischemia, exacerbates hippocampal damage. The present study determines whether GCs endanger hippocampal neurons through the same mechanism by which they damage lymphocytes. GC-induced lymphocytolysis involves cleavage of chromosomal DNA, most likely through steroid induction of a nuclease that produces a characteristic ladder of fragmented DNA. Moreover, inhibition of DNA repair using the poly(ADP-ribose) synthetase inhibitor benzamide exacerbates GC-induced lymphocytolysis. We replicated this GC-induced fragmentation of DNA in thymocytes, but observed the absence of a similar fragmentation in DNA from primary hippocampal cultures under conditions in which GCs exacerbate the toxic effects of the excitotoxin kainic acid. Furthermore, under such conditions benzamide did not worsen the GC/kainic acid toxicity. These observations suggest that GCs endanger hippocampal neurons through a different mechanism, one that seems likely to be less sterotyped and simple than this cascade of apoptosis in lymphocytes.
Masters
J N
JN
Andrus Geronology Center, University of Southern California, Los Angeles 90089-0191.
Finch
C E
CE
Sapolsky
R M
RM
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D005333:Fetus; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins; D051381:Rats; D011919:Rats, Inbred Strains
D001549:Benzamides; D009498:Neurotoxins; D003907:Dexamethasone; D004247:DNA; D007608:Kainic Acid; D003345:Corticosterone