Pre- and Post-Ischemic Administration of Dizocilpine (MK-801) Reduces Cerebral Necrosis in the Rat

Abstract

ABSTRACT: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,l l-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”.

Enhanced Calcium Uptake by CA1 Pyramidal Cell Dendrites in the Postischemic Phase despite Subnormal Evoked Field Potentials: Excitatory Amino Acid Receptor Dependency and Relationship to Neuronal Damage

“…The noncompetitive NMDA receptor antagonist MK-801 (Wong et aI., 1986) was able to reduce the postischemic calcium uptake by approximately 50%, which may explain its neuroprotective effect in some studies (Gill et aI., 1988;Rod and Auer, 1989;Gill and Woodruff, 1990;Swan and Meldrum, 1990). However, administration of the competitive non-NMDA receptor antagonist NBQX (Shear down et aI., 1990a) was able totally to block evoked calcium uptake due to a partial synaptic blockade, in the same dosages as it has been reported to offer powerful neuroprotection Sheardown et al, 1990a, b).…”

“…In our model, the critical postischemic period thus would be after 4-12 h of reflow. However, excitatory amino acid antagonists and VDCC blockers must be adminis tered no later than 1-2 h after the ischemic insult (Rod and Auer, 1989;Diemer et aI., 1990;Swan and Meldrum, 1990;Valentino et aI., 1991) in order to offer neuroprotection. This discrepancy may be due to the fact that in these studies, the drugs were not present in concentrations high enough to reduce calcium uptake during 4-12 h after ischemia.…”

“…Re cent data have shown that ion channels coupled to non-NMDA receptors also have calcium permeabil ity (lino et aI., 1990). In gerbils, postischemic ad ministration of VDCC blocker (Izumiyama and Kogure, 1988) or NMDA receptor antagonists (Boast et aI., 1988;Gill et aI., 1988;Gill and Woodruff, 1990) offer neuroprotection in the CAL Also in rats, there are reports on neuroprotective effects of postischemic administration of VDCC blockers (Deshpande and Wieloch, 1986;Van Re empts et aI., 1986;Valentino et aI., 1991) and NMDA receptor antagonists (Swan et aI., 1988;Rod and Auer, 1989;Swan and Meldrum, 1990). However, other studies in both gerbils and rats show only minor or no neuroprotection with VDCC blockers (Vibulsresth et aI., 1987, Paschen et aI., 1988 or NMDA receptor antagonists (Wieloch et aI., 1988;Nellg a rd and Wieloch, 1992;Buchan et aI., 1991a;Warner et aI., 1991) in the CAL Both VDCCs and NMDA receptor channels re quire depolarization to become permeable to cal cium; this may be achieved by the activation of non NMDA receptors.…”

Regionally Selective Effects of NMDA Receptor Antagonists against Ischemic Brain Damage in the Gerbil

“…A number of findings suggest that this is unlikely. For example, NMDA receptor antagonists have been reported by different groups either to attenuate (Rod and Auer, 1989;Swan and Meldrum, 1990) or not to affect (Wieloch et aI., 1988) brain damage in the rat two-vessel occlusion model of global ischemia. The marked difference between our results with MK-801 in the gerbil and those of Gill and co-workers (Gill et aI., 1987(Gill et aI., , 1988Gill and Woodruff, 1990) reinforces this point.…”

“…Most of the stud ies of MK-801 and other NMDA receptor antago nists that followed, however, yielded less dramatic neuroprotective effects (Boast et aI., 1988;Mar coux et a!. , 1988;Rod and Auer, 1989;Swan and Meldrum, 1990) and in some cases little or no ben eficial effect was obtained (Wieloch et a!. , 1988;Fleischer et a!.…”