INTERLEUKIN-1-BETA AND INTERLEUKIN-1 RECEPTOR ANTAGONIST DO NOT AFFECT GLUTAMATE RELEASE OR CALCIUM-ENTRY IN RAT STRIATAL SYNAPTOSOMES

The cytokine interleukin-1 beta (IL-1 beta) has been implicated in var ious forms of neurodegeneration, and several lines of evidence indicat e that it also modulates synaptic transmission in the central nervous system.(1) Excessive release of the excitatory neurotransmitter L-glut amate results in cell death and probably mediates many neurodegenerati ve conditions.(2) We set out to test the hypothesis that involvement o f IL-1 beta in neurodegeneration results in some interaction with exci tatory amino acid-mediated synaptic transmission in the rat striatum, either by modifying glutamate release or actions. Presynaptic effects of IL-1 beta and the IL-1 receptor antagonist (IL-1ra) on glutamate re lease and calcium entry were investigated in isolated nerve terminals (synaptosomes) prepared from the striatum. In order to evaluate the in volvement of IL-1 in neuronal damage caused by glutamate receptor over -activation, the effect of IL-1ra was studied on N-methyl-D-aspartate (NMDA) and pha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) r eceptor-mediated brain damage in the rat striatum and cortex in vivo. Neither rat recombinant IL-1 beta (rrIL-1 beta: 0.01-2 nM) or human re combinant IL-1ra (hrIL-1ra: 0.2 mu M) had any significant effect on th e KCl-evoked glutamate efflux or calcium entry in striatal synaptosome s, indicating that their actions are unlikely to be presynaptic. In co ntrast, intrastriatal infusion of hrIL-1ra markedly inhibited (by 43-4 6%, P < 0.05) neuronal damage caused by striatal NMDA or AMPA receptor activation in the rat in vivo, whereas no effect was seen on damage i nduced in the cortex. Thus, our data suggest that IL-1 beta and IL-1ra influence neuronal damage in the striatum by acting to modify events that occur after excitatory amino acid receptor activation.