Abstract
Excitatory amino acid receptor-mediated neurotoxicity (excitotoxicity) has been proposed to contribute to neuronal loss in a wide variety of neurodegenerative conditions. Although considerable evidence has accumulated implicating N-methyl-D-aspartate (NMDA), kainate, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the processes of excitotoxicity, relatively little research has focused on the ability of other neurotransmitter systems to influence excitotoxic neuronal injury. In the present study, we examined the effects of trans-1-aminocyclopentyl-1,3-dicarboylic acid (ACPD), a selective agonist for the metabotropic glutamate, or ACPD, receptor, and carbachol, an agonist at the acetylcholine receptor, on neuronal degeneration produced by brief exposure to NMDA in murine cortical cultures. Since excitotoxic neuronal injury is probably caused by increases in intracellular Ca2+ concentrations, the two transmitter agonists were of particular interest as both have been shown to mobilize intracellular calcium stores. Contrary to what might be expected, ACPD and, to a lesser degree, carbachol attenuated NMDA neurotoxicity. The neuroprotective effect of ACPD, but not of carbachol, was dependent upon the developmental state of cultures; in older cultures (greater than or equal to 18 days in vitro), the protective effect decreased. The neuroprotection by ACPD may be, in part, mediated by protein kinases, since protection is partially reversed by the protein kinase antagonists H-7 and HA-1004. These data suggest that concomitant activation of the ACPD receptor may serve as a protective mechanism against neurotoxicity that could be produced by brief intense NMDA receptor activation during normal or abnormal brain function.
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Selected References
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