(Stroke. 1996;27:1624-1628.)
© 1996 American Heart Association, Inc.
Articles |
Inhibitory Effect of MS-153 on Elevated Brain Glutamate Level Induced by Rat Middle Cerebral Artery Occlusion
the Department of Pharmacology, Hamamatsu University School of Medicine (Japan).
Correspondence to Dr K. Umemura, Department of Pharmacology, Hamamatsu University School of Medicine, 3600 Handa-cho Hamamatsu, 431-31 Japan. E-mail umemura@hama-med.ac.jp.
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Abstract |
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Background and Purpose In this study we investigated the effects of a novel compound, MS-153 ([R]-[-]-5-methyl-1-nicotinoyl-2-pyrazoline), on elevated brain glutamate concentrations and cerebral infarct volume induced by middle cerebral artery (MCA) occlusion in the rat.
Methods The rat MCA was occluded by a thrombus induced by a photochemical reaction between green light and the photosensitizer dye rose bengal, which causes endothelial injury followed by formation of a platelet- and fibrin-rich thrombus at the site of photochemical reaction; this method is routinely used in our laboratory to produce arterial occlusion in experimental animals. Extracellular glutamate concentration at the ischemic border zone was determined by a microdialysis technique. The size of cerebral infarction was measured by a histochemical technique 24 hours after MCA occlusion. MS-153 was administered at various doses as a continuous infusion for 24 hours, beginning 0 to 2 hours after MCA occlusion.
Results At the ischemic border zone, the concentration of glutamate in the extracellular fluid increased by 40-fold after ischemia. At 3.13 mg/kg per hour, MS-153 reduced glutamate concentration (P<.05) and also the size of ischemic cerebral infarction (P<.05). Furthermore, the glutamate uptake inhibitor DL-threo-ß-hydroxyaspartate reversed the effect of MS-153 on glutamate concentration.
Conclusions The reduction in the size of cerebral infarction by MS-153 may be attributable to the inhibition of glutamate release or an increase in cellular glutamate uptake.
Key Words: cerebral ischemia, focal • glutamates • middle cerebral artery occlusion • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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Recent studies have indicated that ischemia-induced neuron damage may be linked to the toxicity of excitatory amino acids, particularly glutamate, in the extracellular space.1 2 3 4 5 6 7 8 9 10 11 Based on these studies, the following two strategies may protect neurons against ischemic damage: blockade of postsynaptic excitatory amino acid receptors, such as NMDA and AMPA, which have received considerable attention,12 13 14 15 16 17 18 and more recently, prevention or reduction of an elevated glutamate level in the extracellular fluid.7 8 19 It has been reported that NMDA or AMPA receptor antagonists or the agents that prevent or reduce elevated glutamate levels may protect cortex damage in the ischemic border zone but not neuronal damage in the striatum.7 13 16 Therefore, it is important to investigate the alteration of glutamate concentration in the cortex in the ischemic border zone. In this study glutamate concentration in the cerebral ischemic border zone was measured by a microdialysis technique during ischemia.
MS-153 ([R]-[-]-5-methyl-1-nicotinoyl-2-pyrazoline) has been reported to protect neuronal damage induced by glutamate and NMDA in cultured neurons, without blocking NMDA or AMPA receptors.20 In focal cerebral ischemic models, MS-153 has been protective in experimental cerebral infarction.21 In this study focal ischemic cerebral lesions were induced in the rat by thrombotic occlusion of the MCA to study the protective effect of MS-153 on neuron damage. Using a microdialysis technique, we also determined whether MS-153 reduces glutamate concentration increased by ischemia and whether the glutamate uptake inhibitor TBHA reverses the effect of MS-153 on glutamate concentration.
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Materials and Methods |
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Animal Preparation
Male Wistar rats (SLC, Shizuoka, Japan) weighing 240 to 260 g were used. The body temperature of the animals was maintained at 37.5°C with a heating pad (K-module, model K-20; American Pharmaseal Co). The MCA thrombosis model in the rat has been described previously.22 23 Under 1.5% halothane anesthesia with 30% oxygen, 70% room air, and spontaneous breathing, a catheter for the administration of rose bengal (Wako) or agents was placed in the femoral vein. The left scalp was incised, the temporal muscle was partially cut, and a subtemporal craniotomy was performed with the use of a dental drill under an operating microscope to open a 3-mm-diameter oval bony window, through which only the MCA could be observed. The oval window was irradiated with green light, and the entire irradiated segment of the MCA, including the proximal end of the lenticulostriate branch, became occluded by a thrombus. Photoirradiation with green light (wave length, 540 nm) was achieved with the use of a xenon lamp (L4887; Hamamatsu Photonics) with a heat-absorbing filter and a green filter. The irradiation was directed by a 3-mm-diameter optic fiber mounted on a micromanipulator. The head of the optic fiber was placed on the window in the skull base at a distance of 2 mm above the vessel, providing an irradiation dose of 0.62 W/cm2. Rose bengal (20 mg/kg) was injected intravenously, and photoirradiation was continued for 10 minutes. At the end of the irradiation period, incisions were closed and the anesthesia was discontinued 60 minutes after the operation. Twenty-four hours after irradiation, the cerebrum was blindly removed by another investigator under pentobarbital anesthesia for examination using a microslicer, the cerebrum was coronally sectioned in 1-mm-thick slices from 1.5 mm anterior to 4.5 posterior mm to the bregma, and then six consecutive slices were stained with triphenyltetrazolium chloride (Katayama). The slices were then photographed. For each animal, the ratio of infarction area to the whole area of the corresponding cerebrum was calculated with the use of a computerized image analysis system (Videoplane; Oberkochen).
In pharmacokinetic studies, the half-life of MS-153 has been shown to be approximately 0.7 hour in the rat, and MS-153 crosses the blood-brain barrier well. MS-153 (0.78, 3.13, and 12.5 mg/kg per hour) dissolved in saline was administered intravenously by continuous infusion through the femoral vein for 1 hour immediately after the MCA occlusion under anesthesia; an additional injection was administered intraperitoneally by an osmotic minipump (Alzet; Alza Co) for 23 hours without anesthesia (n=8). Saline was administered in the same manner to a group of eight animals to serve as controls. In another seven animals, MS-153 (12.5 mg/kg per hour) was administered intravenously by continuous infusion through the femoral vein for 1 hour, starting 2 hours after the MCA occlusion; an additional injection was administered intraperitoneally by an osmotic minipump for 21 hours.
Measurement of Glutamate, Glutamine, and Glycine Concentrations in the Brain
A microdialysis probe (CMA/11; Bioanalytical Systems, Inc) was positioned in the ischemic border zone (0.5 mm posterior to the bregma, 4.0 mm lateral to the midline, and 3.0 mm below the surface of the dura). The microdialysis probe was perfused with Ringer's solution (mmol/L: NaCl 147, KCl 4, CaCl2 2.3; pH 7.4) at a flow rate of 2.0 µL/min under anesthesia as described previously.24 The probe position in the ischemic border zone was determined in our previous studies22 23 and was also verified histologically after the experiments. The experiments were started after a 2-hour stabilizing period. The dialysates were collected for each 15-minute perfusion. MS-153 (3.13 mg/kg per hour) or saline was administered by continuous infusion intravenously through the femoral vein for 3 hours after the MCA occlusion. In six different animals, MS-153 (3.13 mg/kg per hour) was continuously administered through the femoral vein during the experiment, Ringer's solution was perfused through the microdialysis probe for the first 90 minutes after MCA occlusion, and then 0.5 mmol/L TBHA in Ringer's solution was perfused through the microdialysis probe for an additional 90 minutes. In six animals not subjected to ischemia, 0.5 mmol/L TBHA in Ringer's solution was perfused through the microdialysis probe for an additional 90 minutes.
Determination of glutamate concentration in the dialysates was by high-performance liquid chromatography equipped with an electrochemical detector (Shimadzu LC-64 system). Derivatives of amino acids were separated on a C18 reverse-phase column (3 µm, HR-80T; Electrochemistry Separations Analysis) and mobilized with 22% methanol, 0.13 mmol/L EDTA, and 0.1 mol/L phosphate buffer (pH 6.4). Concentrations of glutamate in dialysates were calculated with the use of a Chromatopac (C-R4A; Shimadzu).
Determination of Brain Temperature
Brain temperature was measured by a digital thermometer during the MS-153 infusion through the femoral vein or saline infusion in each group of eight animals. The probe of the thermometer (0.5 mm in diameter; Inter Medical) was inserted into the right hemisphere (0.5 mm posterior to the bregma, 4.0 mm lateral to the midline, and 1.0 mm below the surface of the dura) through a cranial window.
Statistical Analysis
Data are presented as mean±SE. Statistical analysis was performed with unpaired Student's t test for comparisons between two groups. Comparisons of more than two groups were made by ANOVA. P<.05 was considered significant.
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Results |
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Physiological variables after the operation were within the normal range. MS-153 did not produce any change in PCO2, PO2, pH in the blood, or mean blood pressure (Table
). Brain temperature was not affected by MS-153 during the experiments.
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Size of Cerebral Infarction
The dorsolateral cortex and striatum were infarcted in the control group. MS-153 (0.78, 3.13, and 12.5 mg/kg per hour) was administered intravenously by continuous infusion for 1 hour starting just after MCA occlusion and then intraperitoneally by an osmotic minipump for 23 hours; this significantly (P<.05) reduced the size of cerebral infarction in the cortex in a dose-dependent manner but not in the striatum (Figs 1 and 2). A similar inhibitory effect on the size of cerebral infarction was observed when MS-153 (12.5 mg/kg per hour) was administered intravenously by continuous infusion for 1 hour starting 2 hours after MCA occlusion and then intraperitoneally by an osmotic minipump for 21 hours (Fig 3).
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) on cerebral infarction in seven animals compared with control group (). MS-153 was administered intravenously by continuous infusion through the femoral vein for 1 hour starting 2 hours after MCA occlusion and then intraperitoneally by an osmotic minipump for 21 hours. Data represent mean±SE of seven animals. *P<.05 vs control group.
Glutamate, Glutamine, and Glycine Concentrations
The concentration of glutamate in the margin of ischemic lesions gradually increased by 40-fold at 90 minutes after MCA occlusion compared with baseline levels and remained high within the 180-minute observation period. MS-153 (3.13 mg/kg per hour), administered as a continuous infusion through the femoral vein, significantly (P<.05) suppressed glutamate concentration increased by ischemia (Fig 4). TBHA, a glutamate uptake inhibitor, significantly (P<.05) increased the glutamate concentration reduced by MS-153 (Fig 4). In six animals not subjected to ischemia, TBHA increased the glutamate concentration to approximately three times the baseline values. The concentration of glutamine was reduced and that of glycine was increased by ischemia in each group treated with saline or MS-153.
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), six animals treated with MS-153 (
), and six animals treated with MS-153 and TBHA (
). Ringer's solution was perfused through the microdialysis probe for the first 90 minutes after MCA occlusion, then 0.5 mmol/L TBHA in Ringer's solution was perfused through the microdialysis probe for an additional 90 minutes. *P<.05 vs control group; #P<.05 vs animals treated with MS-153 and Ringer's solution alone. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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In this study thrombotic occlusion of the MCA was induced by a photochemical reaction between rose bengal and green light, which causes endothelial injury followed by platelet adhesion, aggregation, and formation of a platelet- and fibrin-rich thrombus at the site of the photochemical reaction. Using this model, we investigated whether focal cerebral ischemia induced by MCA occlusion results in an increase in glutamate concentration in the ischemic border zone. The glutamate concentration gradually increased until 90 minutes after MCA occlusion by approximately 40-fold over the baseline level and remained high within the 180-minute observation period. MS-153 reduced the glutamate concentration increased by ischemia, and therefore it is likely that the reduction in the size of cerebral infarction is attributable to the fall in glutamate concentration. The MS-153–induced fall in glutamate concentration was reversed by TBHA, a glutamate uptake inhibitor. In the animals not subjected to ischemia, TBHA also modestly increased glutamate concentration. This suggests that MS-153 may promote cellular uptake of glutamate. However, TBHA did not reverse the glutamate level in the control group, suggesting that MS-153 may also inhibit the release of glutamate. Furthermore, MS-153, which was administered starting 2 hours after MCA occlusion, reduced the size of cerebral infarction 24 hours after MCA occlusion. Administration of TBHA through the dialysis probe was to achieve a high local concentration of TBHA so that glutamate uptake only in the ischemic border zone is inhibited.
Ischemia is known to increase glutamate concentration in the extracellular fluid.3 8 9 10 11 25 The mechanism(s) of the increase in glutamate concentration is attributed to four possibilities: (1) Ca2+-dependent exocytotic release from its intracellular storage pool early during ischemia26 ; (2) imbalance between leakage from the cells and energy-dependent uptake processes27 28 ; (3) reversal of the electrogenic uptake transport systems29 30 ; and (4) cellular lysis. Glutamate can damage nerve cells, promoting neuronal cell death. The reduction in glutamate concentration by MS-153 may be due to inhibition of its release or an increase in glutamate uptake into neurons and glial cells.
On the other hand, Akaike and colleagues20 reported that MS-153, which did not block NMDA or AMPA receptors, produced a protective effect against neuronal cell death induced by glutamate and NMDA in cultured neurons. It has been suggested that excitatory amino acid antagonists can reduce the increases in microdialysate levels of neurotransmitters and other compounds induced by ischemia or hypoglycemia.8 31 The noncompetitive NMDA antagonist MK-801, given systemically, decreased the release of glutamate and aspartate induced by hypoglycemia.31 NMDA antagonists also decreased the release of purine catabolites2 and lactate.26 These effects may be interpreted as a consequence of decreased neuronal or metabolic activity. Lekieffre and Meldrum8 reported that the inhibitory effect of the non–NMDA receptor antagonist GYKI 52466 on the release of glutamate may be mediated by a presynaptic receptor. Although the mechanism(s) of reduction by MS-153 of extracellular glutamate concentration is unclear, it is believed that MS-153 may in part inhibit the release of glutamate by a blockade of intracellular signal transduction, such as inhibition of protein kinase C-
translocation.
In conclusion, the extracellular concentration of glutamate in ischemic neuronal tissue increases very sharply after ischemia and may contribute to cerebral infarction in the early phase of ischemia. The reduction in the size of cerebral infarction by MS-153 may be attributable to the inhibition of glutamate release or an increase in glutamate uptake.
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Selected Abbreviations and Acronyms |
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-amino-3-hydroxy-5-methyl-4-isoxazole
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Acknowledgments |
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The authors thank Dr A.R. Saniabadi for editing the manuscript.
Received February 13, 1996; revision received April 18, 1996; accepted May 15, 1996.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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1. Benveniste H, Drejer J, Schousboe A, Diemer NH. Elevation of the extracellular concentration of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem.. 1985;43:1369-1374.[Medline] [Order article via Infotrieve]
2. Hagberg H, Anderson P, Lacarewicz J, Jacobson I, Butcher S, Sandberg M. Extracellular adenosine, inosine, hypoxanthine, and xanthine in relation to tissue nucleotides and purine in rat striatum during transient ischemia. J Neurochem. 1987;49:227-231.[Medline] [Order article via Infotrieve]
3. Choi DW. Glutamate neurotoxicity and diseases in the nervous system. Neuron. 1988;1:623-634.[Medline] [Order article via Infotrieve]
4. Globus MY, Busto R, Dietrich WD, Martinez E, Valdes I. Intra-ischemic extracellular release of dopamine and glutamate is associated with striatal vulnerability to ischemia. Neurosci Lett. 1988;91:36-40.[Medline] [Order article via Infotrieve]
5. Hillered L, Hallstrom A, Segersvard S, Persson L, Ungerstedt U. Dynamics of extracellular metabolites in the striatum after middle cerebral artery occlusion in the rat monitored by intracerebral microdialysis. J Cereb Blood Flow Metab.. 1989;9:607-616.[Medline] [Order article via Infotrieve]
6.
Butcher SP, Bullock R, Graham DI, McCulloch J. Correlation between amino acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion. Stroke. 1990;21:1727-1733.
7. Smith SE, Lekieffre D, Sowinski P, Meldrum BS. Cerebroprotective effect of BW619C89 after focal or global cerebral ischaemia in the rat. Neuroreport.. 1993;4:1339-1342.[Medline] [Order article via Infotrieve]
8. Lekieffre D, Meldrum BS. The pyrimidine-derivative, BW1003C87, protects CA1 and striatal neurons following transient severe forebrain ischaemia in rats: a microdialysis and histological study. Neuroscience. 1993;56:93-99.[Medline] [Order article via Infotrieve]
9. Tsuyuki YU, Araki H, Yae T, Otomo S. Changes in the extracellular concentrations of amino acids in the rat striatum during transient focal cerebral ischemia. J Neurochem. 1994;62:1074-1078.[Medline] [Order article via Infotrieve]
10. Baldwin HA, Williams JL, Snares M, Ferreria T, Cross AJ, Gree AR. Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat. Br J Pharmacol. 1994;112:188-194.[Medline] [Order article via Infotrieve]
11. Wahl F, Obrenovitch TP, Hardy AM, Plotkine M, Boulu R, Symon L. Extracellular glutamate during focal cerebral ischaemia in rats: time course and calcium dependency. J Neurochem. 1994;63:1003-1011.[Medline] [Order article via Infotrieve]
12.
Simon RP, Swan JH, Griffiths T, Meldrum BS. Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science. 1984;226:850-852.
13. Simon RP, Shiraishi K. N-Methyl-D-aspartate antagonist reduces stroke size and regional glucose metabolism. Ann Neurol. 1990;27:606-611.[Medline] [Order article via Infotrieve]
14.
Sheardown MJ, Nielsen EO, Hansen AJ, Jacobsen P, Honore T. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)quinoxaline: a neuroprotectant for cerebral ischemia. Science. 1990;247:571-574.
15. Gill R, Andline P, Hillered L, Persson L, Hagberg H. The effect of MK-801 on cortical spreading depression in the penumbral zone following focal ischaemia in the rat. J Cereb Blood Flow Metab. 1992;12:371-379.[Medline] [Order article via Infotrieve]
16. Gill R, Nordholm L, Lodge D. The neuroprotective actions of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) in a rat focal ischaemic model. Brain Res. 1992;580:35-43.[Medline] [Order article via Infotrieve]
17. McCulloch J. EAA antagonists and their potential for the treatment of ischaemic brain damage in man. Br J Clin Pharmacol. 1992;34:106-114.[Medline] [Order article via Infotrieve]
18. Bullock R, Graham DI, Swanson S, McCulloch J. Neuroprotective effect of the AMPA receptor antagonist LY-293558 in focal cerebral ischemia in the cat. J Cereb Blood Flow Metab. 1994;14:466-471.[Medline] [Order article via Infotrieve]
19. Arvin B, Lekieffre D, Graham JL, Moncada C, Chapman AG, Meldrum BS. Effect of the non-NMDA receptor antagonist GYKI52466 on the microdialysate and tissue concentrations of amino acids following transient forebrain ischaemia. J Neurochem. 1994;62:1458-1467.[Medline] [Order article via Infotrieve]
20. Akaike A, Tamura Y, Yuko S, Yokota T. Protection by pyrazoline analog MS-153 against glutamate of cytotoxicity in cultured cortical neurons. J Cereb Blood Flow Metab. 1993;13(suppl 1):S663. Abstract.
21. Kawazura H, Takahashi Y, Ohto N, Tamura A. Anti-ischemic effects of MS-153: effects of neurological deficits and cerebral infarction in MCA occluded rats. J Cereb Blood Flow Metab. 1993;13(suppl 1):S699. Abstract.
22.
Umemura K, Wada K, Uematsu T, Nakashima M. Evaluation of the combination of a tissue-type plasminogen activator, SUN9216, and a thromboxane A2 receptor antagonist, vapiprost, in rat middle cerebral artery thrombosis model. Stroke. 1993;24:1077-1081.
23. Umemura K, Wada K, Uematsu T, Mizuno A, Nakashima M. Effect of 21-aminosteroid lipid peroxidation inhibitor, U74006F, in the rat middle cerebral artery occlusion model. Eur J Pharmacol. 1994;251:69-74.[Medline] [Order article via Infotrieve]
24. Gemba T, Matsunaga K, Ueda M. Changes in extracellular concentration of amino acids in the hippocampus during cerebral ischemia in stroke-prone SHR, stroke-resistant SHR and normotensive rats. Neurosci Lett. 1992;135:184-188.[Medline] [Order article via Infotrieve]
25. Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol. 1986;19:105-111.[Medline] [Order article via Infotrieve]
26. Katayama Y, Kawamata T, Tamura T, Hovda DA, Becker DP, Tsubokawa T. Calcium-dependent glutamate release concomitant with massive potassium flux during cerebral ischemia in vivo. Brain Res. 1991;558:136-140.[Medline] [Order article via Infotrieve]
27. Bradford HF, Young AMJ, Crowder JM. Continuous leakage from brain cells is balanced by compensatory high affinity reuptake transport. Neurosci Lett. 1987;81:296-302.[Medline] [Order article via Infotrieve]
28. Shimizu H, Graham SH, Chang LH, Mintorovitch J, James TL, Faden AI, Weinstein PR. Relationship between extracellular neurotransmitter amino acids and energy metabolism during cerebral ischemia in rats monitored by microdialysis and in vivo magnetic resonance spectroscopy. Brain Res. 1993;605:33-42.[Medline] [Order article via Infotrieve]
29. Sarantis M, Attwell D. Glutamate uptake in mammalian retinal glia is voltage- and potassium-dependent. Brain Res. 1990;516:322-325.[Medline] [Order article via Infotrieve]
30. Szatkowski M, Barbour B, Attwell D. Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature. 1990;348:443-446.[Medline] [Order article via Infotrieve]
31. Westerberg E, Kehr J, Ungerstedt U, Wieloch T. The non-competitive NMDA-antagonist MK-801 reduces extracellular amino acid levels during hypoglycemia and protects against hypoglycemic damage in rat neostriatum. Neurosci Res Commun. 1988;3:151-158.
Editorial Comment
Duke University Medical Center, Durham, NC
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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The novel compound MS-153 has been reported to protect against neuronal damage induced by glutamate and NMDA in cultured neurons and in models of cerebral infarction. The study by Umemura and colleagues reports the effects of this agent on extracellular glutamate levels in the ischemic border zone and on infarct volume after MCA thrombosis induced photochemically in rats. MS-153 reduced infarct volume when treatment was started immediately or 2 hours after MCA occlusion and continued throughout the 24-hour survival period. Extracellular glutamate levels were also significantly reduced in MS-153–treated rats. In addition, a glutamate uptake inhibitor increased the glutamate concentration reduced by MS-153 treatment. These interesting findings indicate that MS-153 treatment may reduce glutamate levels and infarct volume by promoting the cellular uptake of glutamate after ischemia.
In this study, infarct volume was significantly reduced whether treatment was started immediately after MCA thrombosis or delayed for 2 hours. In this regard, it would be interesting to determine whether the therapeutic window for MS-153 treatment coincides with extracellular patterns of glutamate normalization after ischemia. A shortcoming of the experimental design is that infarct size was determined at 1 day after ischemia. Recent studies have indicated that longer survival periods may be necessary to critically assess the effects of a therapeutic agent. on infarct size or the frequency of neuronal necrosis. It will therefore be important in future studies to determine whether chronic histopathological protection can be seen with this agent.
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Selected Abbreviations and Acronyms |
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Values are mean±SE. Each data point was measured for 1 hour after the start of administration of MS-153 (12.5 mg/kg per hour) or saline.
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