NEUROPROTECTION BY THE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST CGP-40116 - IN-VIVO AND IN-VITRO STUDIES

The goal of this study was to evaluate the effects of a novel competit ive N-methyl-D-aspartate (NMDA) receptor antagonist, D-(E)-2-amino-4-m ethyl-5-phosphono-3-pentoic acid (CGP 40116), on neuronal damage in vi vo and in vitro. We studied 20 rabbits that underwent a 2-h occlusion of the left internal carotid, anterior cerebral, and middle cerebral a rteries followed by 4 h of reperfusion. Ten minutes after occlusion th e animals were treated with either normal saline (n = 7) or CGP 40116 at two different doses (20 mg/kg, n = 6; 40 mg/kg, n = 7) administered over a 5-min period. Somatosensory evoked potentials were used to con firm adequate ischemia and neuronal injury was assessed by histopathol ogy and magnetic resonance imaging. CGP 40116 decreased cortical ische mic neuronal damage by 74 and 77% (control, 37.8 +/- 13.1%; CGP 20 mg/ kg, 9.9 +/- 3.6%; CGP 40 mg/kg, 8.7 +/- 3.7%; p < 0.01) and reduced co rtical ischemic edema by 52 and 35% (control, 42.3 +/- 10.4%; CGP 20 m g/kg, 20.1 +/- 6.7%; CGP 40 mg/kg, 27.5 +/- 13.3%; p < 0.05) but did n ot protect against striatal injury. We performed a second study using primary cell cultures from mouse neocortex to determine the effects of CGP 40116 on neuronal death induced by a 10-min exposure to 500 mu M NMDA or by 45 min of oxygen-glucose deprivation (OGD). Our results dem onstrate that CGP 40116 was effective at attenuating neuronal death in a concentration-dependent manner (ED(50) of 3.2 mu M against NMDA tox icity and 23.1 mu M against OGD) as measured by lactate dehydrogenase levels 24 h after the insult. The neuroprotective effects of CGP 40116 in vivo and in vitro suggest it may be of potential clinical therapeu tic value.