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 competitive N-methyl-D-aspartate (NMDA) receptor antagonist, D-(E)-2-amino-4-methyl-5-phosphono-3-pentoic acid (CGP 40116), on neuronal damage in vivo and in vitro. We studied 20 rabbits that underwent a 2-h occlusion of the left internal carotid, anterior cerebral, and middle cerebral arteries followed by 4 h of reperfusion. Ten minutes after occlusion the 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 confirm adequate ischemia and neuronal injury was assessed by histopathology and magnetic resonance imaging. CGP 40116 decreased cortical ischemic 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 cortical ischemic edema by 52 and 35% (control, 42.3 +/- 10.4%; CGP 20 mg/kg, 20.1 +/- 6.7%; CGP 40 mg/kg, 27.5 +/- 13.3%; p < 0.05) but did not 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 microM NMDA or by 45 min of oxygen-glucose deprivation (OGD). Our results demonstrate that CGP 40116 was effective at attenuating neuronal death in a concentration-dependent manner (ED50 of 3.2 microM against NMDA toxicity and 23.1 microM against OGD) as measured by lactate dehydrogenase levels 24 h after the insult.(ABSTRACT TRUNCATED AT 250 WORDS)
Maier
C M
CM
Department of Neurosurgery, Stanford University School of Medicine, CA 94305, USA.
Sun
G H
GH
Kunis
D M
DM
Giffard
R G
RG
Steinberg
G K
GK
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011817:Rabbits; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D015763:2-Amino-5-phosphonovalerate; D005947:Glucose