[(S)-ALPHA-PHENYL-2-PYRIDINE-ETHANAMINE DIHYDROCHLORIDE], A LOW-AFFINITY UNCOMPETITIVE N-METHYL-D-ASPARTIC ACID ANTAGONIST, IS EFFECTIVE INRODENT MODELS OF GLOBAL AND FOCAL ISCHEMIA

[(S)-Alpha-phenyl-2-pyridine-ethanamine dihydrochloride] (ARL 15896AR) is a low affinity uncompetitive N-methyl-D-aspartic acid receptor ant agonist that was tested in animal models of anoxia and ischemia. Pretr eatment of rodents with ARL 15896AR extended survival time during expo sure to hypoxia. With the rat four-vessel occlusion model of global is chemia (20 min), oral dosing commencing at reflow, resulted in signifi cant protection of the CA1 hippocampal neurons. ARL 15896AR was, howev er, ineffective in the rat two-vessel occlusion model and in the gerbi l models of forebrain ischemia, the latter due to an inability to atta in 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 u p to 1 hr post-MCAO significantly reduced cortical infarct volume. The ability of ARL 15896AR to influence infarct size, as well as function al correlates was examined in SHR after 90 min of MCAO. T-2 weighted m agnetic resonance images taken at 2 and 6 days post-MCAO revealed sign ificantly smaller lesion sizes in the group receiving injections with ARL 15896AR beginning 30 min after occlusion. Spontaneously hypertensi ve rats were subsequently tested (30-42 days post-MCAO) and found to b e deficient in skilled use of the forepaws (staircase test). The contr alateral forepaw was most severely impaired, however, ARL 15896AR trea tment prevented motor impairment in only the ipsilateral forepaw. Hist opathological examination of cortical infarct size was unremarkable be tween treated and control rats. The findings indicate that ARL 15896AR exhibits neuroprotection in global and focal models of ischemia.