Inhibition of the Glutamate Dependent Activation of the Nmda Receptor By Adenosine in Cortical Tissue of the Newborn Piglet. 17

Hypothesis: Adenosine will competitively inhibit the glutamate site and decrease the glutamate dependent activation of the NMDA receptor ion-channel. Methods: Studies were performed in brain cell membranes from 6 normoxic (Nx) and 6 hypoxic (Hx) newborn piglets. ³H-MK-801 binding was performed in the presence of 0 to 10μM glutamate and 100μM glycine as an index of NMDA receptor activation. Assays were performed in the presence and absence of 100μM adenosine. Results: Maximum binding(mean ± sd) was 238 ± 25nM/mg protein in untreated Nx membranes as compared with 155 ± 23 nM/mg protein in the treated Nx group, a 35% decrease of NMDA receptor activation. Ka (concentration of glutamate needed for 50% of maximum activation) was 0.22μM glutamate in untreated, Nx tissue vs 0.31 μM glutamate in treated, Nx tissue, an increase of 40%. In Hx tissue, untreated samples showed maximum binding of 216 ± 34 nM/mg protein as compared with 124 ± 33 nM/mg protein (42% inhibition of activation). Hx Ka values were 0.32 μM glutamate in untreated samples and 0.36 μM glutamate in treated samples, an increase of 11%.Conclusions: Adenosine inhibits the NMDA receptor ion-channel activation, probably by interacting at the glutamate site of the receptor. The altered response in the hypoxic tissue indicates a modification of the glutamate site on the receptor during hypoxia. The NMDA receptor ion-channel mediated effect of adenosine appears to be a new mechanism of its action, resulting in inhibitory neurotransmission by counteracting the excitatory pathway.