LIPOCORTIN-1 INHIBITS NMDA RECEPTOR-MEDIATED NEURONAL DAMAGE IN THE STRIATUM OF THE RAT

Lipocortin-1 (annexin-1), an endogenous phospholipid and calcium binding protein, has been shown to significantly attenuate the damage produced by focal cerebral ischaemia in the rat. In the present study we have therefore investigated its effect on N-methyl-D-aspartate (NMDA) induced neuronal damage. Unilateral intrastriatal infusion of a potent and selective NMDA agonist, cis-2,4-methanoglutamate (MGlu), induced an extensive lesion of the striatum in the rat, which was inhibited ( > 80%) by prior injection of MK801 (4 mg/kg, i.p.). Infusion of 1.2-mu-g of an active fragment of lipocortin-1 (N-terminal 1-188 aa) immediately after MGlu significantly reduced the extent of damage by 44.2+/-8.0%. In contrast, infusion of 3-mu-l of neutralizing anti-lipocortin-I antibody with MGlu increased lesion size by 158.9+/-22.0%. These findings indicate that the damage produced by intrastriatal infusion of MGlu is mediated by the NMDA receptor. Lipocortin-1 fragment markedly attenuated, and the neutralizing antibody increased, this NMDA mediated neuronal damage. These observations may explain the neuroprotective action of lipocortin following cerebral ischaemia.