Neuroprotection by N-methyl-D-aspartate antagonists in focal cerebral ischemia is dependent on continued maintenance dosing.
While N-methyl-D-aspartate antagonists have been shown to attenuate neuronal damage in focal cerebral ischemia, few studies have examined whether continuous or multiple dose treatment is necessary for maximum efficacy. We studied the effect of a loading dose only or load plus maintenance infusion using several non-competitive N-methyl-D-aspartate antagonists (dextromethorphan, dextrorphan, MK-801) and the levorotatory enantiomer of dextromethorphan (levomethorphan) in a rabbit model of focal cerebral ischemia. Forty-seven anesthetized rabbits underwent occlusion of the left internal carotid, anterior cerebral and middle cerebral arteries for 2 h followed by 4 h of reperfusion. Drugs were administered 10 min after occlusion. Dextromethorphan and dextrorphan protected against ischemic edema only when given as load plus maintenance (29% and 31% reduction, respectively), while both load only and load plus maintenance of MK-801 protected against edema (26% and 31% reduction, respectively). Levomethorphan load plus maintenance also protected against ischemic edema (25% reduction). However, dextromethorphan and dextrorphan both required maintenance infusion to protect against ischemic neuronal damage (24% and 27% reduction in area of ischemic neuronal damage, respectively), while levomethorphan failed to protect against neuronal injury even when given as load plus maintenance. Administration of MK-801 as load plus maintenance reduced ischemic neuronal damage by 23%, but this difference was not quite statistically significant. These results suggest that processes of ischemic damage, such as excitotoxic injury, continue for several hours beyond the initial period of focal ischemia, and that non-competitive N-methyl-D-aspartate antagonists require more prolonged administration to achieve neuroprotection.(ABSTRACT TRUNCATED AT 250 WORDS)
Steinberg
G K
GK
Department of Neurosurgery, Stanford University School of Medicine, CA 94305, USA.
Yoon
E J
EJ
Kunis
D M
DM
Sun
G H
GH
Maier
C M
CM
Grant
G A
GA
D000818:Animals; D001831:Body Temperature; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology; D002545:Brain Ischemia / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D002540:Cerebral Cortex / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D003915:Dextromethorphan; D003917:Dextrorphan; D006863:Hydrogen-Ion Concentration; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents; D010100:Oxygen / Q000097:blood; D011817:Rabbits
D018696:Neuroprotective Agents; D003917:Dextrorphan; D016202:N-Methylaspartate; D003915:Dextromethorphan; D010100:Oxygen