The purpose of this study was to determine the effectiveness of the non-competitive
N-methyl-D-aspartate receptor antagonist
dizocilpine, or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-
imine (MK-801) in mitigating ischemic neuronal
necrosis in the rat. Ten minutes of transient forebrain
ischemia was induced by a combination of bilateral carotid clamping and
hypotension to 50 mm Hg. Control animals received intravenous saline, whereas treated animals received
dizocilpine, either 1 mg/kg iv 20 min. pre
ischemia, 1 mg/kg iv 20 min. post
ischemia, 10 mg/kg iv 20 min. post
ischemia, 10 mg/kg ip 2 hrs. post
ischemia, 10 mg/kg
ip 24 hrs. post
ischemia. The groups receiving
dizocilpine before or up to 20 min. after
ischemia all showed a significant reduction in the number of dead neurons as assessed by quantitative histopathology in hippocampus, caudate nucleus and cerebral cortex after one week of recovery. However,
dizocilpine administered either 2 or 24 hrs. after
ischemia afforded no protection. These results suggest that the potent non-competitive
NMDA antagonist
dizocilpine may have some value in protecting the brain from hippocampal and cortical neuronal
necrosis after a short insult consisting of dense
transient cerebral ischemia. Noteworthy is the fact that pharmacologic intervention in the post-ischemic period was successful in preventing neuronal death, provided that
drug administration occurred within
dizocilpine's "therapeutic window".