Experimental Study of Initiation of Cortical Spreading Depression by Excitatory Amino Acids Using a New Topical Application Model

Park, Jung Yui; Park, Youn Kwan; Chung, Yong Gu; Chung, Hung Seob; Lee, Ki Chan; Lee, Hoon Kap

Abstract

The purpose of this study was, first, to devise a new model for topical application of excitatory amino acids(EAAs) to rat cerebral cortex that successfully and repeatdly initiate the cortical spreading depression(CSD). Then, by using this model, six major EAAs that are known to act on single or multiple subtypes of EAA receptor were examined; glutamate, kainate, aspartate, N-methyl-D-aspartate(NMDA), quisqualate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazoie-proprite(AMPA). Through the model, with a cone-shaped well buried in 1.5mm depth of the cerebral cortex, these chemical agents were topically applied to the cortical gray matter. A total of 50 Sprague-Dawley rats were used and divided into seven groups including the sham group. Doses of each EAA between 10(-7) and 10(-4)M concentrations were escalated for triggering the CSD and its rate of consistency in triggering was also evaluated. In the overall results. CSDs were repeatedly initiated in all experimental groups with relatively consistent rates. Duration of CSDs were 1-4 minutes(mean 2.2+/-1.4) and amplitudes were 20-40mV. Effective dose(50)(ED(50)), that trigger over 50% of CSD was 10(-5)M(n=8) for glutamate, 10(-7)M(n=8) for aspartate, 10(-5)M(n=7) for AMPA, 10(-5)M(n=7) for quisqualate, and 10(-4)M(n=7) for NMDA and kainate group. Among those acting on the single receptor, AMPA was shown to be the most effective in triggering CSD, and NMDA, and kainate were in descending orders. Aspartate that was known to act on multiple EAA receptors, showed the highest rate of triggering CSD among all groups, but glutamate, known to act on all receptors of its subtypes, showed the most consistent rate of triggering CSD at dose escalation. These results revealed that those EAA acting on multiple receptors, namely aspartate and glutamate, showed the highest and most consistent rate of triggering CSD. Among those acting on single channel of receptors. AMPA was the most effective, although its consistency and rate of triggering of CSD was somewhat lower than.