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 ne uronal damage in focal cerebral ischemia, few studies have examined wh ether continous or multiple dose treatment is necessary for maximum ef ficacy. We studied the effect of a loading dose only or load plus main tenance infusion using several non-competitive N-methyl-D-aspartate an tagonists (dextromethorphan, dextrorphan, MK-801) and the levorotatory enantiomer of dextromethorphan (levomethorphan) in a rabbit model of focal cerebral ischemia. Forty-seven anesthetized rabbits underwent oc clusion of the left internal carotid, anterior cerebral and middle cer ebral arteries for 2 h followed by 4 h of reperfusion. Drugs were admi nistered 10 min after occlusion. Dextromethorphan and dextrorphan prot ected against ischemic edema only when given as load plus maintenance (29% and 31% reduction, respectively), while both load only and load p lus maintenance MK-801 protected against edema (26% and 31% reduction, respectively). Levomethorphan load plus maintenance also protected ag ainst ischemic edema (25% reduction). However, dextromethorphan and de xtrorphan both required maintenance infusion to protect against ischem ic 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. Administrat ion of MK-801 as load plus maintenance reduced ischemic neuronal damag e by 23%, but this difference was not quite statistically significant. These results suggest that processes of ischemic damage, such as exci totoxic injury, continue for several hours beyond the initial period o f focal ischemia, and that non-competitive N-methyl-D-aspartate antago nists require more prolonged administration to achieve neuroprotection . This may have important implications for understanding the pathophys iological mechanisms of ischemic neuronal death as well as the treatme nt of clinical stroke using these drugs.