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.