licostinel and Brain-Infarction

The glycine site, N-methyl-D-aspartate antagonist 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA1021) was previously tested only in models of transient stroke with pre-treatment paradigms. We therefore tested whether it would protect in two models of permanent stroke in two rat strains with delayed treatment. Intravenous ACEA1021 reduced cerebral infarction by 62% (15 min treatment delay) and 42% (2 h treatment delay), relative to vehicle-injected rats, when subjected to a modified Tamura and permanent intraluminal filament model of stroke, respectively. In comparison, intravenous nicotinamide (500 mg/kg), which was tested in separate animal cohorts, had no significant effect on infarction. These data show that ACEA1021 protects against permanent focal cerebral ischemia, even with a 2 h post-treatment delay. Characterization of the therapeutic window with longer outcome times including infarction and neurobehavioral endpoints is needed.

Topics: Animals; Brain; Brain Infarction; Infarction, Middle Cerebral Artery; Injections, Intravenous; Male; Neuroprotective Agents; Quinoxalines; Rats; Rats, Inbred F344; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Time Factors

The neuroprotective activity of ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione; licostinel), a selective antagonist at the strychnine-insensitive glycine site associated with the NMDA receptor complex, has been investigated in various models of focal cerebral ischemia. In isoflurane-anaesthesised Wistar rats with permanent ipsilateral carotid artery ligation and transient middle cerebral artery occlusion (duration of occlusion, 2 h) followed by reperfusion (24 h), intravenous administration of ACEA 1021 (bolus: 10 mg/kg, 15 min after the onset of middle cerebral artery occlusion; infusion: 7 mg/kg/h for 6 h beginning 30 min after occlusion of the artery) produced a 32% reduction in infarct volume. Similarly, in Sprague-Dawley rats with transient middle cerebral artery occlusion (2 h) followed by 24 h of reperfusion, identical treatment with ACEA 1021 decreased infarct size by 39%. Magnetic resonance imaging (MRI) confirmed these effects in the transient model, in that infarct volume observed using apparent diffusion coefficient (ADC) maps was significantly smaller after 24 h in the ACEA 1021-treated rats compared with Tris-treated controls. Furthermore, the increase in perfusion signal intensity after reperfusion was more pronounced in the ACEA 1021-treated rats than in controls. In Fisher 344 rats with permanent occlusion of the middle cerebral artery, ACEA 1021 induced a dose-related decrease in infarct volume, which was associated with an improvement in neurological outcome as measured by the rope suspension procedure. Administration of the same dose regimen, as above, in Fisher rats with permanent middle cerebral artery occlusion reduced infarct volume by 68%. This dose was as effective when administration was delayed for 2 h. In mice with permanent middle cerebral artery occlusion, ACEA 1021 (5 mg/kg, i.v., 5 min after occlusion; 30 mg/kg, s.c., 1 and 4 h post-middle cerebral artery occlusion) decreased infarct size by 42%. The consistent anti-ischemic effects of ACEA 1021 make it a valuable compound for exploratory stroke research.

Topics: Animals; Behavior, Animal; Brain; Brain Infarction; Brain Ischemia; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intravenous; Injections, Subcutaneous; Magnetic Resonance Imaging; Male; Mice; Neuroprotective Agents; Psychomotor Performance; Quinoxalines; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reperfusion