Neurotoxic effect of high dose of L-(+)-2-amino-3-phosphonopropionic acid in rats after intracaudatal injection.
OBJECTIVE
To investigate neurotoxic effect of L-(+)-2-amino-3-phosphonopropionic acid (L-AP3), a partial agonist/antagonist of metabotropic glutamate receptors (mGluRs), and explore the underlying mechanisms.


METHODS
Consciousness and behavior of rats were evaluated after injection of L-AP3, D-(+)-2-amino-3-phosphonopropionic acid (D-AP3, an isomer of L-AP3) or L-(+)-2-amino-4-phosphonobutyric acid (L-AP4, an agonist of mGluRs) into right caudatum. Brain water, Na+, K+, and Ca2+ contents as well as the permeability of blood brain barrier (BBB) were determined 6 h after treatment of these chemicals. Histological changes at the same time point were also observed.


RESULTS
Rats treated with L-AP3 600 nmol but not 60 nmol became somnolentia. Inject ion of L-AP3 600 nmol induced a great increase of brain water, Na+, and Ca2+ contents, and a decrease of brain K+ content (P < 0.01). Meanwhile, the permeability of BBB was also increased (P < 0.01). Electron microscopic study revealed remarkable swelling of astrocytes and degenerative changes of neurons in chemical-treated caudatum. The neurotoxic effect of L-AP3 was not mimicked by D-AP3 or L-AP4 (P < 0.05). DL-2-Amino-5-phosphonovaleric acid, an antagonist of N-methyl-D-aspartate (NMDA) receptors, attenuated the changes induced by L-AP3 (P < 0.05), whereas (+/-)-alpha-methyl-(4-carboxyphenyl)glycine, a non-subtype specific antagonist of mGluRs, failed to block the effect of L-AP3.


CONCLUSIONS
Intracaudatal injection of L-AP3 induced neurotoxic effect characterized by vasogenic brain edema, neuronal degeneration, and high brain Ca2+ content. Neurotoxic effect of L-AP3 was stereoselective and might be mediated by phospholipase C activation and partially involvement of NMDA receptors.
Yuan
F
F
Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing 100050, China. yuanff@sina.com
Wang
T Y
TY
Xu
L X
LX
Sun
Y L
YL
Luo
L
L
Qu
B Q
BQ
D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000648:ultrastructure; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001929:Brain Edema / Q000139:chemically induced*; D002118:Calcium / Q000378:metabolism; D002421:Caudate Nucleus / Q000648:ultrastructure*; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000633:toxicity; D007278:Injections, Spinal; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C000211:2-amino-3-phosphonopropionic acid; D000409:Alanine; D002118:Calcium