The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats

Abstract

The neuroprotective effects of dizocilipine maleate (MK-801), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor/channel, were tested in the 4-vessel occlusion rat model of forebrain ischemia. Adult Wistar rats, treated intraperitoneally with MK-801 or saline using several different treatment paradigms were subjected to 5 (n = 208) or 15 (n = 62) min of severe, transient forebrain ischemia. In saline-treated animals, 15 min of ischemia (n = 13) produced extensive and consistent loss of pyramidal neurons in the CA1 zone of hippocampus. The degree and distribution of cell loss were not reduced by single dose preischemic administration of MK-801 at 1 (n = 7), 2.5 (n = 4), or 5 mg/kg (n = 8). In other animals subjected to 15 min of forebrain ischemia, multiple doses of MK-801 (5, 2.5, and 2.5 mg/kg) given immediately and at approximately 8 and 20 hr after cerebral reperfusion (n = 5) did not alter CA1 injury compared to saline-treated controls (n = 5). Five minutes of forebrain ischemia in saline-treated animals, (n = 82) resulted in significantly fewer (p less than 0.001) dead CA1 pyramidal cells and a greater variance compared to animals subjected to 15 min of ischemia. Power analysis of the preliminary saline-treated animals subjected to 5 min of ischemia (n = 22) indicated that 60 animals per group were necessary to detect a 15% difference between MK-801 and vehicle-treated groups. Multidose treatment with MK-801 (1 mg/kg) given 1 hr prior to 5 min of ischemia (n = 60) and again at approximately 8 and 16 hr after recirculation failed to attenuate hippocampal injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of MK801 on evoked potentials, spinal cord blood flow and cord edema in acute spinal cord injury in rats

“…In the present study, we chose to administer MK801 systemically with a relatively higher dose of 7.5 mg/mg, at which all the animals in MK801-treated group survived well during the 4 h period of observation. Furthermore, considering the 1 h plasma half-life time of MK801 in rats, 45 we treated the animals with MK801 repetitively before and after SCI, bilateral CAO with hypotension 67 ± 69 or vertebral artery occlusion in rats 70,71 pretreatment: 0.1 ± 10 mg/kg, iv/ip 67,71 neuronal damage and microglial activation 72 reduced microglial activation and neuronal death of CA1 72 or did not prevent neuronal damage 67,71 67,71,72 posttreatment: 0.1 ± 5.0 mg/kg, ip/iv, immediately 20 h after reperfusion 67,71 neuronal damage and working memory 70 no neuroprotection 67,68,71 or decreased cell loss within 5 h injection after ischemia 69 and injected the drug slowly (16 min/infusion). MK801 delivered in this way has been shown to produce neuroprotection in experimental cerebral ischemia.…”

Neuroprotective and antioxidant potential of terpenoid fraction fromHygrophila auriculataagainst transient global cerebral ischemia in rats

“…The effect was statistically significant (p < 0.05). However, vitamin E and TF 100 mg/kg showed an increase in neuronal density in the CA1 field of the tGCI rat brain but it was not found to be statistically significant (Buchan et al, 1991).…”

“…Rectal temperature was maintained at 37 ± 0.5°C during the surgical procedures to avoid hypothermia. Sham operated animals were treated similarly to the ischemic group but the common carotid and vertebral arteries were not occluded (Buchan et al, 1991).…”

“…Analysis of neuronal density was performed in hippocampal sectors CA1 using the images taken at 400× magnification. The number of intact neurons in the hippocampal CA1 subfield per mm of the pyramidal cell layer was counted by a blinded investigator according to the method of Buchan et al (1991). The neuronal density for a given animal represents the average of both the right and left neuronal cell densities.…”

MK-801 (Dizocilpine) Protects the Brain from Repeated Normothermic Global Ischemic Insults in the Rat

“…nist of NMDA-induced excitotoxicity Rod and Auer, 1989), subsequent work disclosed prolonged hypothermia in MK-801-treated isch emic animals, which was required for its therapeu tic effect (Buchan and Pulsinelli, 1990;Corbett et al, 1990). In an extensive study, a protective effect of MK-801 could not be demonstrated in tempera ture-regulated normothermic rats exposed to 5 or 15 min of four-vessel occlusion despite the use of a wide range of MK-801 dosing regimens (Buchan et al, 1991). We and others have shown that mild de grees of brain hypothermia, by itself, are markedly protective in ischemia (Busto et al, 1987(Busto et al, , 1989aMinamisawa et al, 1990a,b;Chopp et al, 1991;Ginsberg et al, 1992) and that this is related, at least in part, to the inhibition of glutamate release (Busto et al, 1990), as well as protection against blood brain barrier dysfunction (Dietrich et al, 1990 Intriguingly, it has been in animal models of focal cerebral ischemia that the most convincing evi dence of MK-801 's cerebroprotective efficacy has emerged (Kochhar et al, 1988;Ozyurt et al, 1988;Park et al, 1988a,b;Dirnagl et al, 1990;Bielenberg and Beck, 199 1;Gill et al, 1991;Buchan et al, 1992;Roussel et aI., 1992).…”