Neurotoxic Effect of High Dose of L-(+)-2-amino-3-phosphonopropionic Acid in Rats After Intracaudatal Injection

F Yuan, T Y Wang, L X Xu, Y L Sun, L Luo, B Q Qu

Acta Pharmacol Sin. 2001 Jun;22(6):556-60.

PMID: 11747764

Abstract:

Aim:




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.













Conclusion:




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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP23052815-A	L-(+)-2-Amino-4-phosphonobutyric acid		23052-81-5	Price