RESUMEN
The monofilament technique of transient middle cerebral artery occlusion (MCAO) was used in 3 separate studies to evaluate the efficacy of the low-affinity, use-dependent N-methyl-d-aspartate receptor antagonist, AR-R15896AR. First, a dose-response curve was attempted. Wister Kyoto rats received 2 hours of MCAO. Five minutes later, a 30-minute intravenous infusion of AR-R15896AR was given, followed by subcutaneous implantation of Alzet minipumps that were calibrated to maintain specified plasma levels (approximately 682, 1885, or 2682 ng/mL) of AR-R15896 (free base) for 1 week. The highest plasma level attained significantly decreased the percentage of damage to the subcortex, cortex, and total brain. Second, the high-dose, 1-week treatment regimen was repeated to determine if neuroprotection would extend to 8 weeks after MCAO. Indeed, in separate groups of animals, significant reduction in the percentage of damage, which was generally confined to the cortex and subcortex, was observed at 1, 2, 4, and 8 weeks. Third, verification was achieved in another laboratory. Lister Hooded rats received 60 minutes of transient MCAO. At 70 minutes, an acute dose of AR-R15896AR (20.3 mg/kg) was injected intraperitoneally and the rats were killed 23 hours later. This treatment group also exhibited significant reduction in the volume of infarction in the subcortex, cortex, and total brain. The outcome of these investigations supports the ongoing Phase II clinical trials in patients with acute stroke.
RESUMEN
Use-dependent N-methyl-D-aspartate (NMDA) receptor antagonists protect neurons from the lethal consequences of excessive stimulation by excitatory amino acids. Clinical development of high-affinity compounds such as MK801 have been limited due to untoward side effects. Toward this end, the lower-affinity use-dependent NMDA antagonists have greater margins of safety and have advanced to clinical trials for stroke, epilepsy, head trauma and chronic neurodegenerative disorders. AR-R 15896AR is currently in Phase II trials for stroke and has been repeatedly demonstrated to afford neuroprotection in a variety of in vivo and in vitro models associated with ischemia/excitotoxic conditions.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/uso terapéutico , Hipoxia/tratamiento farmacológico , Isquemia/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Piridinas/uso terapéutico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Corteza Cerebral/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Humanos , Ratones , N-Metilaspartato/farmacología , Fármacos Neuroprotectores/sangre , Fármacos Neuroprotectores/farmacocinética , Piridinas/sangre , Piridinas/farmacocinética , Ratas , Ratas Endogámicas SHRAsunto(s)
Antagonistas de Aminoácidos Excitadores/farmacología , Ataque Isquémico Transitorio/prevención & control , Fármacos Neuroprotectores/farmacología , Piridinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Gatos , Hipoxia Encefálica/fisiopatología , Hipoxia Encefálica/prevención & control , Ataque Isquémico Transitorio/fisiopatología , Ratones , Canales de Potasio/fisiología , Ratas , Canales de Sodio/fisiologíaRESUMEN
[(S)-Alpha-phenyl-2-pyridine-ethanamine dihydrochloride] (ARL 15896AR) is a low affinity uncompetitive N-methyl-D-aspartic acid receptor antagonist that was tested in animal models of anoxia and ischemia. Pretreatment of rodents with ARL 15896AR extended survival time during exposure to hypoxia. With the rat four-vessel occlusion model of global ischemia (20 min), oral dosing commencing at reflow, resulted in significant protection of the CA1 hippocampal neurons. ARL 15896AR was, however, ineffective in the rat two-vessel occlusion model and in the gerbil models of forebrain ischemia, the latter due to an inability to attain suitable plasma levels. In the spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) (2 hr plus 22 hr reflow), acute dosing with ARL 15896AR (i.p.) beginning from 30 min before or up to 1 hr post-MCAO significantly reduced cortical infarct volume. The ability of ARL 15896AR to influence infarct size, as well as functional correlates was examined in SHR after 90 min of MCAO. T2 weighted magnetic resonance images taken at 2 and 6 days post-MCAO revealed significantly smaller lesion sizes in the group receiving injections with ARL 15896AR beginning 30 min after occlusion. Spontaneously hypertensive rats were subsequently tested (30-42 days post-MCAO) and found to be deficient in skilled use of the forepaws (staircase test). The contralateral forepaw was most severely impaired, however, ARL 15896AR treatment prevented motor impairment in only the ipsilateral forepaw. Histopathological examination of cortical infarct size was unremarkable between treated and control rats. The findings indicate that ARL 15896AR exhibits neuroprotection in global and focal models of ischemia