Protection by NMDA Antagonists against Selective Cell Loss following Transient Ischaemia

Swan, Jeanette H.; Meldrum, Brian S.

doi:10.1038/jcbfm.1990.63

Cited by 159 publications

(59 citation statements)

References 35 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Tator

1999

Spinal Cord

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Objectives: To determine whether MK801, an NMDA receptor antagonist, blocks glutamate excitotoxicity directly or via other mechanisms such as improving blood supply at the injury site in a rat model of spinal cord injury (SCI). In the present study, the e ects of pre-and posttreatment with MK801 on axonal function, spinal cord blood¯ow (SCBF) and cord water content were studied after acute SCI in rats. Methods: Somatosensory evoked potentials (SSEPs) and cerebellar evoked potentials (CEPs) were used to quantify electrophysiological function, and the hydrogen clearance technique and wet-dry weight measurements were used to measure SCBF and cord water content, respectively. Twenty rats received a 21 g clip compression injury of the cord at T1, and were then randomly and blindly allocated to either MK801 or saline groups. Each rat received an intravenous infusion of drug or saline four times during the experiment (16 min/infusion) with the ®rst infusion (MK801 3 mg/kg) beginning 8 min pre-injury, and the other infusions (MK801 1.5 mg/kg) at 1 h intervals after injury. Control experiments on uninjured rats were performed in 10 rats using the same procedure as above except the clip compression injury of the cord was omitted. Results: In the MK801 groups with or without SCI, the amplitude of the evoked potential peaks, especially the SSEPs, was signi®cantly lower than in the saline group. There were no di erences in SCBF or cord water content between the MK801 and saline groups. Conclusion: Pre-and posttreatment with MK801 inhibits evoked potentials, but does not improve SCBF or cord edema after acute compression SCI in rats. For the ®rst time it has been shown that MK801 produced a blockade of glutamate excitatory transmission in a erent pathways after SCI. Further work is required to determine whether this inhibition is reversible and related to neuroprotection and functional recovery after SCI.

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Section: Discussionmentioning

confidence: 99%

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

Tator

1999

Spinal Cord

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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

Andiné

Jacobson

Hagberg

1992

J Cereb Blood Flow Metab

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After 6–12 h of recovery from transient cerebral ischemia, the pyramidal cells of the hipppocampal CA1 region take up excessive amounts of calcium upon electrical stimulation, which has been suggested to be important for the development of delayed neuronal death. The aim of this study was to further characterize this enhanced calcium uptake with respect to time-course of development, relationship to neuronal damage, and amplitude of evoked field potentials as well as the dependency on N-methyl-d-aspartate (NMDA) and non-NMDA receptors. Adult Wistar rats were used and calcium-sensitive microelectrodes were placed in the stratum radiatum of the CA1 hippocampus for recording of the extracellular calcium concentration ([Ca2+]ec) during 20 min of ischemia and for 6 h of reflow. High-frequency stimulation of the perforant pathway elicited burst firing in CA1 and a transient decrease in [Ca2+]ec which reflects neuronal uptake. Shifts in [Ca2+]ec could not be evoked 0–1 h after ischemia. However, from 1–2 h burst firing could be evoked and the accompanying shift in [Ca2+]ec increased thereafter in amplitude with prolonged reflow, exceeded preischemic levels after 4 h, and reached 250 ± 116% (mean ± SD) of control after 6 h of reflow ( p < 0.05). The extracellular reference potential shift during electrical stimulation and the amplitude of evoked field potentials were still subnormal after 6 h [85 ± 25% and 83 ± 25%, respectively (mean ± SD)]. There was a significant correlation between the degree of stimulated calcium uptake at 6 h postischemia and the extent of CA1 damage evaluated 7 days after the ischemic insult ( r = 0.849; p < 0.001). The shifts in [Ca2+]ec were reduced by the NMDA antagonist MK-801 (0.5–2 mg/kg, i.v.) to approximately 50% of the initial level during both control and postischemic conditions ( p < 0.01). The non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[ F]quinoxaline (NBQX) (42 ± 13 mg/kg, i.p.; mean ± SD) decreased the amplitude of the evoked field potentials (to 30 ± 28% of control, p < 0.05) and completely abolished the evoked shifts in [Ca2+]ec. In conclusion, the uptake of calcium into CA1 pyramidal cells during electrical stimulation was enhanced already 4 h after ischemia in spite of the fact that other measures of excitability were subnormal. This calcium uptake correlated to the extent of CA1 pyramidal cell damage and was dependent on both NMDA and non-NMDA receptor activation.

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“…MK-801 has been shown to interfere with a vari ety of pathological processes. Besides its remark able beneficial effect on infarct size after permanent vascular occlusion (Ozyurt et aI., 1988;Park et aI., 1988;Dirnagl et aI., 1990), it reduces neuronal in jury after severe hyperglycemia (Papagapiou and Auer, 1990) and improves the survival ratio of py ramidal neurons in the CAl sector of hippocampus after brief periods of global ischemia (Gill et aI., 1988;Kass et aI., 1989;Swan and Meldrum, 1990), although the latter has been related mainly to its temperature-lowering effect (Buchan and Pulsinelli, 2 h MeA occlusion 1990; Corbett et aI., 1990). It inhibits spontaneous electrocortical activity in a dose-dependent way (Marquis et aI., 1989), and it suppresses cortical spreading depression induced by electrical stimula tion (Marrannes et aI., 1989).…”

Section: ��--------------------[mentioning

confidence: 99%

Repeated Negative DC Deflections in Rat Cortex following Middle Cerebral Artery Occlusion are Abolished by MK-801: Effect on Volume of Ischemic Injury

Iijima

Mies

Hossmann

1992

J Cereb Blood Flow Metab

347

147

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Summary: Following permanent occlusion of the left middle cerebral artery (MCA) in rats, electrophysiologi cal and hemodynamic characteristics of the periinfarct border zone were investigated in sham-operated (n = 6), untreated (n = 6), and MK-801-treated 0.0 mg/kg; n = 6) animals. For this purpose, direct current potential (DC), EEG, and blood flow (laser-Doppler flowmetry) were re corded from the cortex in the periphery of the MCA ter ritory. In sham-operated rats, a single negative cortical DC deflection was observed after electrocoagulation of the cortex, whereas in untreated MCA-occluded animals, three to eight transient DC det1ections were monitored during the initial 3 h of ischemia. The duration of these cortical DC shifts gradually increased from 1.2 ± 0.3 to 3.7 ± 2.7 min (mean ± SD; p < 0.05) during this time. In animals treated intraperitoneally with MK-801 (3.0 mgt According to the classic concept of the threshold relationship between the density of ischemia and neuronal injury, different flow thresholds have been identified for the suppression of membrane poten tials and the suppression of neuronal transmission (Astrup et aI., 1977). Tissue perfused at a flow rate between these thresholds is referred to as the isch emic penumbra because the neurons in this area are thought to be functionally inactive but still viable (Astrup et aI., 1981 ). Threshold determinations of brain metabolism have revealed that the flow rate

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Protection by NMDA Antagonists against Selective Cell Loss following Transient Ischaemia

Cited by 159 publications

References 35 publications

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

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

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

Repeated Negative DC Deflections in Rat Cortex following Middle Cerebral Artery Occlusion are Abolished by MK-801: Effect on Volume of Ischemic Injury

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