THE SIGMA-RECEPTOR LIGAND JO-1784 (IGMESINE-HYDROCHLORIDE) IS NEUROPROTECTIVE IN THE GERBIL MODEL OF GLOBAL CEREBRAL-ISCHEMIA

To assess the effects of the novel a receptor ligand JO 1784 hyl-N-met hyl-1,4-diphenyl-1-yl-but-3-en-1-ylamine, hydrochloride or igmesine hy drochloride) on behavioural and histological changes following cerebra l ischaemia, the gerbil model of cerebral ischaemia was used. Two expe riments were carried out. In the first animals were either sham operat ed, subjected to 5 min of bilateral carotid occlusion or administered JO 1784 (25, 50, 75 or 100 mg/kg p.o.) 1, 24 and 48 h after 5 min bila teral carotid occlusion and histological evaluation carried our 96 h a fter surgery. In the second experiment the effects of JO 1784 administ ered at a dose of 100 mg/kg i.p. 30 min, 6, 24 and 48 h post-surgery o n home cage activity and nitric oxide (NO) synthase activity in the co rtex, hippocampus, cerebellum and brain stem 4 days after surgery was examined. Extensive neuronal death was observed in the CA1 region of 5 min occluded animals. JO 1784 (50, 75 and 100 mg/kg) provided signifi cant protection against this ischaemia-induced cell death (P < 0.03-0. 005). In the second experiment a large increase in home cage activity was observed for 5 min occluded animals for 12 h after surgery (P = 0. 0018-0.02). A large increase in NO synthase activity was observed in a ll brain regions for 5 min occluded animals. Post-administration of JO 1784 attenuated the ischaemia-induced hyperactivity and increased NO synthase activities. These results show that the selective a receptor ligand JO 1784 is neuroprotective in the gerbil model of cerebral isch aemia and indicates that a receptor ligands may be useful in preventin g ischaemia-induced neurodegeneration.