Pharmacologic Studies of the Neuroprotective Actions of a Glutamate Antagonist in Ischemia

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Abstract
Ischemia may increase glutamate release, which can lead to neuronal damage. The therapeutic value of drugs that antagonize glutamate's effects are being investigated in CNS ischemia. This study examined the efficacy of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine hydrogen maleate], in reducing ischemic injury. We explored the limits of this therapy and different properties of MK-801 that might be involved in its neuroprotective actions. Two focal CNS ischemia models were used, a multiple cerebral embolic model (MCEM) and a rabbit spinal cord ischemia model (RSCIM). When animals were treated 5 minutes after the onset of injury, MK-801 was effective in reducing ischemic damage in both models. However, when treatment was delayed 10 minutes after the ischemic insult in the MCEM, no neuroprotection was observed even when the MK-801 dose was increased eightfold. We also did not find a beneficial effect of MK-801 pretreatment with a dose that was one tenth of the effective dose in the RSCIM. Studies using the (-) MK-801 isomer showed that MK-801 neuroprotection exhibited stereoselectivity. The contribution of anticonvulsant activity and sedation to MK-801's neuroprotective actions was examined indirectly using phenytoin and midazolam, respectively. Neither drug was effective in reducing ischemic injury in the MCEM. This suggests that MK-801's neuroprotective efficacy in ischemia is mediated through its NMDA receptor antagonist activity independent of its anticonvulsant or sedative properties. These results support the hypothesis that excessive NMDA receptor excitation may be involved in ischemic neuronal damage.