Gliotoxic properties of the Lathyrus excitotoxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (beta-L-ODAP).
beta-N-Oxalyl-L-alpha,beta-diaminopropionic acid (beta-L-ODAP) is an excitatory amino acid agonist found in the seeds of Lathyrus sativus that is believed to be the major causative agent in the pathology of human lathyrism. We have found that in addition to its previously recognized neurotoxic properties, beta-L-ODAP is also gliotoxic. When added to cultures of neonatal rat astrocytes, beta-L-ODAP induced a series of morphological changes (e.g., extensive vacuole formation, pale and swollen nuclei with obvious nucleoli, and cellular swelling) that led to the eventual lysis of the glial cells. If the beta-L-ODAP was removed prior to the lysis of the astrocytes, many of the early morphological changes appeared to be reversible. When quantitated by a loss of the lactate dehydrogenase activity, beta-L-ODAP lysed the astrocytes with an LD50 of 2.1 +/- 0.2 mM following 48 h of exposure. Lower concentrations of beta-L-ODAP were found to be more toxic if the duration of the exposure was increased. The results suggest that the overall impact of the toxin on the CNS may represent the cumulative action of beta-L-ODAP at a number of distinct points on both neurons and astrocytes. The potential that these multiple sites of action may affect the normal regulation of extracellular glutamate and, consequently, disturb the balance between its normal and pathological roles is discussed.
Bridges
R J
RJ
Department of Neurology, Irvine Research Unit on Brain Aging, University of California 92717.
Hatalski
C
C
Shim
S N
SN
Nunn
P B
PB
D000599:Amino Acids, Diamino / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D015394:Molecular Structure; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000599:Amino Acids, Diamino; D009498:Neurotoxins; C100126:oxalyldiaminopropionic acid