dizocilpine-maleate and Brain-Edema

To explore the mechanism and type of acute infectious brain edema induced by injection of pertussis bacilli (PB) in rat neocortex, to study the neuroprotective effect of non-competitive antagonist of N-methl-D-aspartate (NMDA) receptor (MK-801) and antagonist of Ca(2+) channels (nimodipine) on brain edema, and to investigate the relationship between percentage of water content and cytosolic free calcium concentration ([Ca(2+) ](i)) in synaptosomes or content of Evans Blue (EB).. 95 SD rats were randomly divided into five groups, ie, normal control group, sham-operated control group, PB group, nimodipine treatment group and MK-801 pretreatment group. The acute infectious brain edema was induced by injection of PB into the rats. Quantitative measurements of water content and the concentration of EB were performed. [Ca(2+) ](i) was determined in calcium fluorescent indication Fura-2/AM loaded neuronal synaptosome with a spectrofluorophotometer. To observe the effect of MK-801 and nimodipine, we administered MK-801 48 hours and 24 hours before the injection of PB in MK-801 pretreatment group, and nimodipine after the injection of PB in nimodipine treatment group. The specific binding of NMDA receptor was measured with [(3)H]-MK-801 in the neuronal membrane of cerebral cortex.. The levels of water content and EB content of brain tissues, and [Ca(2+) ](i) in the neuronal synaptosomes increased more significantly in the PB-injected cerebral hemisphere in the PB group than those of normal control group and sham-operated control group (P<0.05). The water content and [Ca(2+) ](i) increased with the duration of infectious brain edema. Nimodipine administered after the injection of PB could significantly decrease the water content, EB and [Ca(2+) ](i) (P<0.05). MK-801 could significantly decrease the water content, EB and [Ca(2+) ](i) in 4 h and 24 h groups (P<0.05). The Kd values were 30.5 nmol/L+/-3.0 nmol/L and 42.1 nmol/L+/-4.2 nmol/L in PB group and NS group respectively (P<0.05), and Bmax were 0.606 pmol/mg.pro+/-0.087 pmol/mg.pro and 0.623 pmol/mg.pro+/-0.082 pmol/mg.pro respectively, without statistical significance (P>0.05).. The changes in the permeability of blood-brain barrier (BBB) and Ca(2+)-overload may participate in the pathogenesis of infectious brain edema. Treatment with nimodipine can dramatically reduce the damage of brain edema and demonstrate neuroprotective effect on brain edema by inhibiting the excess of Ca(2+) influx and reducing the permeability of BBB. MK-801 pretreatment may inhibit the delayed Ca(2+) influx into the neurons. The infectious brain edema is not only cytotoxic brain edema (intracellular edema) but also vasogenic brain edema (extracellular edema) followed by earlier BBB breakdown, so infectious brain edema is complicated with brain edema.

Topics: Acute Disease; Analysis of Variance; Animals; Blood-Brain Barrier; Bordetella pertussis; Brain Edema; Calcium; Calcium Channel Blockers; Dizocilpine Maleate; Nimodipine; Rats; Rats, Sprague-Dawley

Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.

Topics: Animals; Blood-Brain Barrier; Body Temperature; Brain; Brain Edema; Cerebrovascular Circulation; Disease Progression; Dizocilpine Maleate; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Galactosamine; Glomerular Filtration Rate; Hepatic Encephalopathy; Hyperammonemia; Intracranial Hypertension; Inulin; Kidney; Lactates; Liver Failure; Liver Regeneration; Male; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Time Factors

A new series of ionone derived allylic alcohols have been evaluated for anti-ischemic activity. Out of them, 12f and 13b decreased infarct volume to 23.98+/-4.7 mm3 and 93.98+/-24.8 mm3 as compared to ischemic group.

Topics: Animals; Apoptosis; Brain Edema; Brain Ischemia; Cell Survival; Drug Design; Male; Molecular Structure; Neurons; Neuroprotective Agents; Norisoprenoids; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship

Glutamate antagonists are very attractive drugs in laboratory works to protect neural tissue against ischemia. In this work, the effects of magnesium, MK-801 and combination of magnesium and MK-801 on blood-brain barrier (BBB) and brain edema after experimentally induced traumatic brain injury are evaluated.. A standard closed head injury was induced on the rats by a controlled impact device using a 450-g free falling mass from a height of 2 m onto a metallic disc fixed to the intact skull. One of the following was injected to animals intraperitoneally 30 minutes after injury: saline, magnesium, MK-801 and magnesium plus MK-801. To quantify the brain edema, the specific gravity of the brain tissue was determined. To demonstrate the alteration of the BBB permeability, Evans blue dye was used as a tracer.. In all treatment groups, the specific gravity of brain tissue values was significantly higher compared with the control group. Evans blue dye content in the brain tissue was significantly reduced in all three treatment groups with respect to the control group. There was no significant difference of effect between the groups of magnesium alone and MK-801 alone when compared with each other and when compared with their combination.. The present data demonstrate that treatment with magnesium, MK-801 and combination of magnesium and MK-801 can reduce formation of brain edema and can help restore BBB permeability after experimental diffuse brain injury.

Topics: Animals; Blood-Brain Barrier; Body Water; Brain Edema; Brain Injuries; Diffuse Axonal Injury; Disease Models, Animal; Dizocilpine Maleate; Drug Combinations; Drug Synergism; Evans Blue; Head Injuries, Closed; Indicators and Reagents; Magnesium Compounds; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Specific Gravity; Treatment Outcome

Fibrinolytic therapy for spontaneous intracerebral hemorrhage using recombinant tissue plasminogen activator (rtPA) is considered a viable alternative to microsurgical hematoma removal. However, experimental data suggest that rtPA is neurotoxic and evokes a late perihematomal edema. We present preliminary data focusing on the avoidance of late edema formation after lysis of an intracerebral hematoma in a porcine model.. Twenty pigs underwent placement of a frontal intracerebral hematoma with a minimum volume of 1 mL. Half of the pigs were subjected to rtPA clot lysis and MK-801 injection for blockage of the NMDA receptor-mediated rtPA-enhanced excitotoxic pathway. The remaining 10 pigs received desmoteplase (DSPA) for clot lysis, which is known to be a less neurotoxic fibrinolytic agent than rtPA. MRI on the day of surgery and on postoperative days 4 and 10 was used to assess hematoma and edema volumes.. Late edema formation could be prevented in both the MK-801/rtPA and DSPA pigs.. The benefits of fibrinolytic therapy for intracerebral hematomas appear to be counterbalanced by late edema formation. MK-801 infusion as an adjunct to rtPA lysis, or the use of DSPA instead of rtPA, prevents late edema and therefore has the potential to further improve results after clot lysis.

Topics: Animals; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Dizocilpine Maleate; Hematoma; Magnetic Resonance Imaging; Neuroprotective Agents; Plasminogen Activators; Swine; Thrombolytic Therapy; Time Factors

Cerebral ischemia due to secondary injuries plays an important role in the high mortality rate of acute subdural hematoma (SDH). Although promising results were obtained from experimental works with excitatory amino acid (EAA) antagonists which inhibit the excitotoxic mechanism in the development of cerebral ischemia, these agents could not be used clinically due to their psychomimetic side effects. Memantine, also an EAA antagonist, has been used for a long time in the treatment of different neurodegenerative diseases; however, it was not used in treatment of acute subdural hematoma before. This study has been designed to investigate the development of cerebral ischemia and ischemic edema under experimental acute subdural hematoma and the effect of memantine (Sigma M-9292) and MK-801 (Sigma M-107) in the treatment of ischemia.. Forty-two adult female Sprague-Dawley rats were divided into two groups: Group A for investigation of ischemia related to SDH and its treatment, and Group B for investigation of cerebral edema. Both groups were further divided into five subgroups, i.e. for sham operations, formation of SDH and treatment with saline, MK-801 and memantine. Treatment of cerebral edema could not be investigated because formation of cerebral edema could not be proven statistically. For evaluation of ischemia, the ratio of ischemic area/the total brain area was calculated as percentages in coronal slices of the rats' brains.. In all of the evaluated slices, statistical analysis showed that treatment with MK-801 as well as memantine reduced ischemia caused by SDH.. Our study showed that memantine, which is already considered as a safe treatment alternative for other central nervous system (CNS) diseases, can be useful in the treatment of acute SDH as well.

Topics: Animals; Brain Edema; Brain Ischemia; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Functional Laterality; Hematoma, Subdural, Acute; Memantine; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric

Fibrinolytic therapy with recombinant tissue plasminogen activator (rtPA) is considered a treatment option in patients with deep-seated intracerebral hemorrhage (ICH). Nevertheless, the results of animal experiments have shown that tPA exerts pleiotropic actions in the brain, including regulation of vasoactivity, amplification of calcium conductance by cleavage of the N-methyl-D-aspartate (NMDA) receptor subunit, and activation of metalloproteinases, which increase excitotoxicity, damage the blood-brain barrier, and worsen edema. The authors investigated whether the noncompetitive NMDA receptor antagonist MK801 can be used as an adjuvant therapy in combination with rtPA to attenuate the unfavorable delayed edema formation and inflammation observed following rtPA therapy in an experimental porcine model of ICH.. Twenty pigs were used in this study; MK801 (0.3 mg/kg) was administered to each pig intravenously immediately after hematoma induction and on the 1st and 3rd day after hematoma induction. Ten of the 20 pigs were randomly assigned to fibrinolytic therapy with rtPA (MK801-tPA group), whereas in the remaining 10 control animals (MK801 group) the hematomas were allowed to follow their natural courses of resorption. The extent of edema formation was evaluated using magnetic resonance (MR) imaging volumetry on Days 0, 4, and 10 after hematoma induction and was compared with histopathological changes found at necropsy. The mean edema volumes in these two groups were also compared with that in the group of nine pigs examined in a preceding experimental series, in which the animals' hematomas were only treated with rtPA (tPA group). In the 10 animals in the MK801-tPA group, the mean perihematoma edema volume on MR images had not significantly increased by Day 4 (p < 0.08) or Day 10 (p < 0.35) after hematoma induction. In the 10 animals in the MK801 group, the increase in mean perifocal edema size was significant after 4 days (p < 0.001) and nonsignificant after 10 days (p < 0.09). In the nine animals in the tPA group, the mean edema volume significantly increased by Days 4 (p < 0.002) and 10 (p < 0.03).. As suggested by the reduction in delayed edema volume and the inflammatory response, MK801 modifies the neurotoxic properties of rtPA but not those of blood degradation products. Possibly, fibrinolytic therapy of ICH is more beneficial if combined with agents such as MK801.

Topics: Animals; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Dizocilpine Maleate; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Fibrinolytic Agents; Infusions, Intravenous; Male; Receptors, N-Methyl-D-Aspartate; Swine; Tissue Plasminogen Activator

In recent years, serum S100B has been used as a secondary endpoint in some clinical trials in which serum S100B has successfully indicated the benefits or harm done by tested agents. However, few reports describe serum S100B as an indicator of the efficiency of neuroprotective treatment in experimental stroke models, although serum S100B may be as useful for histological and functional evaluations of neuroprotective treatments as in clinical trials. The present study seeks to investigate the possibility that serum S100B reflects successful combined treatment with rt-PA and MK-801 in an embolic stroke rat model. An embolic stroke model of rats was produced via intra-arterial autologous clot injection, after which serum S100B levels were measured 24 h after embolism and the association of serum S100B levels with brain edema volume and infarct volume investigated. Combination treatment with rt-PA and MK-801 significantly attenuated the elevation of serum S100B, which correlated significantly with reductions in brain edema resulting from combination treatment. These findings suggest that serum S100B is a simple and objective indicator for successful neuroprotective therapy and would help seeking partners for combination treatments with rt-PA in an embolic stroke rat model. Assessments of the efficacy of combination treatments with rt-PA and neuroprotectants using serum S100B would facilitate translational research bridging laboratory and bedsides because serum S100B functions as a common marker in both rats and human patients suffering from ischemic stroke.

Topics: Animals; Brain Edema; Brain Infarction; Disease Models, Animal; Dizocilpine Maleate; Drug Therapy, Combination; Fibrinolytic Agents; Laser-Doppler Flowmetry; Male; Nerve Growth Factors; Neuroprotective Agents; Rats; Regional Blood Flow; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Stroke; Thromboembolism; Tissue Plasminogen Activator

The pre-ischaemic neuroprotective potential of a novel polyamine/NMDA antagonist N1-dansyl-spermine (1-5 mg kg(-1)) was studied in a transient focal cerebral ischaemia model in mice in comparison to a reference compound, MK-801 (1 or 3 mg kg(-1)). The intraluminal suture transient middle cerebral artery occlusion (MCAO) model was used. N1-dansyl-spermine and MK-801 were administered (i.p.) 30 min prior to ischaemia. A range of histological and behavioural assessments was employed. N1-dansyl-spermine had a comparable effect to MK-801 at reducing the percentage hemisphere lesion volume (%HLV) at the doses tested. Furthermore, N1-dansyl-spermine reduced the ischaemic brain oedema, which MK-801 did not. N1-dansyl-spermine significantly reversed the decrease of locomotor activity (LMA) caused by the MCAO and showed a significant effect at improving the rotarod performance impaired by MCAO. In contrast, MK-801 had no beneficial effect on sensorimotor function and even worsened the LMA. These results clearly demonstrate the pre-ischaemic neuroprotective effect of N1-dansyl-spermine in a transient focal cerebral ischaemia model.

Topics: Animals; Brain; Brain Edema; Dansyl Compounds; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Mice; Motor Activity; Neuroprotective Agents; Rotarod Performance Test; Spermine; Tetrazolium Salts; Time Factors

In vitro studies suggested that tissue plasminogen activator (t-PA) may aggravate ischemic injury by enhancing N-methyl-D-aspartate (NMDA) receptor signalling. It remained unclear whether NMDA signalling is also relevant for t-PA toxicity in vivo. We herein examined effects of intravenous t-PA (10 mg/kg), administered alone or in combination with the NMDA antagonist MK-801 (0.2 mg/kg), following 90 min of middle cerebral artery occlusion in mice. In our study, MK-801 alone, administered intraperitoneally, neither affected infarct volume nor brain swelling at 24 h after reperfusion. t-PA significantly increased infarct size, in accordance with previous findings. t-PA-induced ischemic injury was completely abolished and brain swelling markedly reduced when t-PA-treated animals received additional MK-801 injections. To elucidate how t-PA influences brain damage, we examined actions of t-PA on the expression of NO synthases by immunohistochemistry, showing that t-PA does not influence neuronal NO synthase, but increases inducible NO synthase in ischemic areas. The effect of t-PA on inducible NO synthase levels was completely reversed after cotreatment with MK-801. Our study provides in vivo evidence in a model of focal cerebral ischemia that t-PA-induced brain injury involves an NMDA receptor-dependent mechanism.

Topics: Analysis of Variance; Animals; Blood Gas Analysis; Brain Edema; Brain Ischemia; Disease Models, Animal; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Agonists; Immunohistochemistry; Laser-Doppler Flowmetry; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Tissue Plasminogen Activator

Massive glutamate release is an important factor leading to ionic imbalance after occlusive stroke, which in turn contributes to cytotoxic edema formation. Currently, measurements of cytotoxic edema using 'diffusion weighted' MRI, is being used in human stroke studies, as a 'surrogate' end point for neuroprotective drug trials, including studies with glutamate antagonists. However, it is not fully understood to what extent glutamate-mediated N-methyl-D-aspartate (NMDA) receptor activation is related to 'cytotoxic' edema formation, and thus, to what degree apparent diffusion coefficient (ADC) changes, assessed by magnetic resonance imaging with 'ACD mapping', represent NMDA receptor activation. To study this relationship, four cats underwent permanent middle cerebral artery occlusion (MCAO). Edema formation was investigated using MRI with 'ACD mapping', while NMDA receptor activation was simultaneously detected in the same animals, using radio labeled 125IodoMK-801, which binds only in activated and open NMDA channels. At 5 h post-occlusion, a large area of edema could be found with significantly lower ADC values in the core and penumbral area of the ischemic lesion when compared to contralateral values. On corresponding sections of the feline brains, increased 125I-MK-801 binding was found in the infarct penumbra. However, there was no significant topographical correlation between ADC values and measured radioactivity. The results indicate that there is not a significant linkage between NMDA receptor activation and 'cytotoxic' edema following permanent MCAO. The detection of a large area of NMDA channel activation within regions of low ADC does however indicate an area of 'penumbral' ischemia susceptible to treatment with NMDA channel blockers.

Topics: Animals; Autoradiography; Brain Edema; Cats; Diffusion Magnetic Resonance Imaging; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Infarction, Middle Cerebral Artery; Iodine Radioisotopes; Male; Radionuclide Imaging; Receptors, N-Methyl-D-Aspartate

Acute subdural hematoma (SDH) is the most common mass lesion in severe head injury, and brain ischemia is the leading pathophysiological mechanism in the development of secondary brain damage following SDH. Hypothermia has been employed as an effective neuroprotective procedure in clinical and laboratory studies on cerebral ischemic and contusional injuries. In the present study, we used a rat acute SDH model to assess the effect of hypothermia on the intracranial pressure (ICP) and also on the brain edema formation at 4 h after hematoma induction. Mild (34 degrees C) and moderate (32 degrees C) hypothermia did not significantly affect the ICP or cerebral perfusion pressure, but they were associated with a significant lower cortical brain edema formation beneath the hematoma (81.09 +/- 0.49%, p<0.05; and 80.88 +/- 0.17%, p<0.01) when compared with the normothermic control group (81.65 +/- 0.52%). This reduction in brain edema formation was comparable to the results of MK-801 treatment (80.95 +/- 0.35%, p<0.01). The present findings indicate that hypothermia represents a potent neuroprotective strategy. The possible protective mechanisms of hypothermic protection afforded in this rat acute SDH model are discussed.

Topics: Animals; Brain; Brain Edema; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hematoma, Subdural; Hyperthermia, Induced; Intracranial Pressure; Male; Rats; Rats, Sprague-Dawley

N-methyl-D-aspartate (NMDA) receptor antagonists have been found to be protective after cerebral ischemia. However most of these drugs have limited value as neuroprotectives in clinical therapy because of their side effects. Memantine is a noncompetitive NMDA receptor antagonist and it has been used for the treatment of various cerebral disorders with relatively few side effects. We investigated the beneficial effects of Memantine and compared its effect with MK-801 in a temporary focal cerebral ischemia model. As cerebral ischemia model three hours middle cerebral artery occlusion (MCAO) with intraluminal thread and three hours reperfusion was used. 78 male Spraque-Dawley rats were divided into three groups as follows: Control (Saline), treatment 1 (MK-801), and treatment 2 (Memantine) groups. In the treated groups, 15 minutes after MCAO, MK-801 and Memantine were administered in amounts of 1 mg/kg and 10 mg/kg intraperitoneally respectively. After a 3 hour period of reperfusion, the animals were examined for neurological deficits and then killed. The following values were measured; cerebral water content, blood brain barrier (BBB) permeability at the core and periphery of the ischemic hemisphere and contralateral hemisphere and infarct volumes. The severity of neurological deficit (p < 0.001) and infarct volume (p < 0.001) was reduced in both Memantine and MK-801 treated groups compared with saline treated groups. Memantine attenuated brain edema formation and BBB permeability at the periphery (p < 0.01), MK-801 both at the core (p < 0.05) and the periphery (p < 0.01) of the ischemia. These results demonstrated that the NMDA receptor antagonists Memantine and MK-801 were neuroprotective when given 15 min after MCAO in temporary focal cerebral ischemia.

Topics: Animals; Brain Edema; Brain Ischemia; Dizocilpine Maleate; Dopamine Agents; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Infusions, Parenteral; Male; Memantine; Rats; Rats, Sprague-Dawley

Cold injury model in rat was used to determine the effect of treatment with the competitive NMDA antagonists CPP and the non-competitive NMDA antagonist MK-801 in cerebral oedema. MK-801 was applied in doses of 1 mg/kg and CPP of 10 mg/kg, 15 min. after injury. Control animals received 1 ml saline at the same time interval after injury. Tissue samples from the core and periphery of the lesion of the injured hemisphere and from the symmetrical location of the undamaged contralateral hemisphere were removed 24 hours after injury. Blood brain barrier permeability, brain water content and tissue specific gravity values were determined. MK-801 was found beneficial for reducing the oedema and restore the blood brain barrier permeability at the penumbral zone of the lesion, whereas both MK-801 and CPP were found ineffective for prevention of oedema accumulation at the core of the lesion.

Topics: Analysis of Variance; Animals; Blood-Brain Barrier; Body Water; Brain Edema; Cold Temperature; Disease Models, Animal; Dizocilpine Maleate; Evans Blue; Excitatory Amino Acid Antagonists; Male; Neuroprotective Agents; Piperazines; Rats; Rats, Sprague-Dawley; Specific Gravity

Adult rats intubated with a single dose of ethanol (alcohol; approximately 5 g/kg) for 5 to 10 successive days incur neurodegeneration in the entorhinal cortex, dentate gyrus, and olfactory bulbs accompanied by cerebrocortical edema and electrolyte (Na+, K+) accumulation. The brain damage is not lessened by cotreatment with the NMDA receptor antagonist MK-801; also, as reported elsewhere, MK-801 as well as non-NMDA receptor and Ca2+ channel antagonists are not neuroprotective in a similar, but more compressed, intoxication protocol. However, cotreatment with the electrolyte transport inhibitor/diuretic furosemide reduces alcohol-dependent cerebrocortical damage by 75-85% while preventing brain hydration and electrolyte elevations; olfactory bulb neurodegeneration is not attenuated. In parallel in vitro studies, rat organotypic entorhinal/hippocampal slice cultures exposed to alcohol (50-200 mM) 15 h/day for 6 days, mirroring episodic intoxication in vivo, demonstrate concentration-related release of the cytotoxic indicator, lactate dehydrogenase. Analogous to the in vivo findings, furosemide blocks this alcohol-induced in vitro cytotoxicity. Our results showing neuroprotection by furosemide indicate that brain edema and swelling are essential events in the brain damage induced by episodic alcohol exposure. Furosemide and related agents might be useful as neuroprotective agents in alcohol abuse. We suggest that the neurodegeneration is elicited in part by edema-dependent oxidative stress, but the regional selectivity of the damage may be best explained by physical (mechanical) compression of the limbic cortex against the adjacent tympanic bulla and subsequent neuronal cytoskeletal collapse. A scheme for these apparently nonexcitotoxic metabolic and mechanical pathways initiated by repeated alcohol exposure is proposed.

Topics: Alcoholic Intoxication; Animals; Brain; Brain Edema; Dentate Gyrus; Diuretics; Dizocilpine Maleate; Entorhinal Cortex; Ethanol; Excitatory Amino Acid Antagonists; Furosemide; Male; Nerve Degeneration; Neuroprotective Agents; Olfactory Bulb; Organ Culture Techniques; Organ Specificity; Potassium; Rats; Rats, Sprague-Dawley; Sodium

The hexachlorophene-induced cytotoxic brain oedema is an experimental model of brain damage, suitable for testing cerebroprotective substances (Andreas 1993). In order to examine whether glutamate receptors are involved in mediating functional disorders due to neurotoxic brain damage, we have studied the protective effects of several competitive and non-competitive antagonists using adult male Wistar rats in a simple "ladder-test" for assessing coordinative motor behaviour. Hexachlorophene-induced brain damage was verified by histological examination of the cerebellum with vacuolation of white matter, astrocyte hypertrophy and astrocyte proliferation taken as signs of neurotoxic injury. The non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine maleate (MK-801) decreased the motor disturbance on the first and second day of the "ladder-test" when applied in the doses 0.1 mg/kg and 0.2 mg/kg intraperitoneally for 3 weeks during the hexachlorophene treatment. Acute MK-801 administration (0.1 mg/kg intraperitoneally) after 3 weeks hexachlorophene exposure improved the coordinative motor response only on the first day. When testing the competitive NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) in the dose 1.0 mg/kg intraperitoneally the motor disturbance was lowered significantly earlier than in spontaneous remission. Similar effects were observed with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the dose of 0.8 mg/kg intraperitoneally, an antagonist interacting both with the strychnine-insensitive binding site for glycine within the NMDA receptor complex and with the kainate(+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor complex. Concurrent MK-801 administration decreased the vacuolation of white matter. The results suggest that NMDA receptors and non-NMDA receptors are involved in development of functional disorders induced by hexachlorophene.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Brain; Brain Edema; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hexachlorophene; Male; Rats; Rats, Wistar; Receptors, Glutamate

The experimental evidence linking glutamate to ischemic neuronal injury is derived from in vitro or in vivo animal stroke models. We, therefore, developed an in vitro preparation to determine whether glutamate contributes to early neuronal swelling in oxygen and glucose deprived (OGD) human neocortical slices. In order to monitor neuronal swelling, we measured extracellular tissue resistance in brain slices by passing constant current pulses through two electrodes and recording the voltage drop between them. We verified that NMDA (30 microM) or OGD induced a rise in tissue resistance in rat neocortical slices. We then examined human neocortical slices from 11 patients undergoing resections for intractable epilepsy. Both the rodent and human neocortical slices swelled within 10 min of OGD. In both, the glutamate antagonist dizocilpine (MK-801) reduced the swelling. In the rats, MK-801 (5 microM) prolonged the latency to onset of neuronal swelling following OGD from 7.6 +/- 0.6 min (mean +/- S.E.M., n = 16) to 17.4 +/- 2.6 min (n = 6; p < 0.01). Other putative neuroprotective agents were much less effective in this paradigm. In the human slices, MK-801 again prolonged the latency to resistance increase from 8.6 +/- 0.4 min (n = 8) to 17.2 +/- 1.7 min (n = 9, p < 0.01). This is the direct demonstration that glutamate receptor activation leads to neuronal swelling in substrate deficient human brain. These results, which are similar to those obtained in the rodent brain slices, help validate the animal slices as appropriate models for the study of OGD in human brain.

Topics: Animals; Brain Edema; Cerebral Cortex; Dizocilpine Maleate; Electric Impedance; Excitatory Amino Acid Antagonists; Female; Glucose; Humans; Hypoxia; In Vitro Techniques; Male; Neuroprotective Agents; Neurotoxins; Rats

The purpose of the present study was to compare the characteristics of the photochemical-induced thrombotic occlusion model and the thermocoagulated occlusion model of the middle cerebral artery in rats. We evaluated the neuroprotective effects of a NMDA receptor antagonist, (+)-MK-801 (dizocilpine, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-imine), an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, YM90K (6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione monohydrochloride), a Ca2+ channel antagonist, S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)-thieno[2 ,3-b]pyridine-5-carboxylate), the radical scavengers, MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one) and EPC-K1 (L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-tridecyl)-2H-1-be nzopyran-6yl-hydrogen phosphate] potassium salt), and a calcineurin inhibitor, FK506 (tacrolimus, Prograf). Although all tested agents in the present study attenuated the brain damage in the photochemical-induced thrombotic occlusion model, the radical scavengers did not attenuate the brain damage in the thermocoagulated occlusion model. The time course of brain damage and brain edema formation in the two models was examined. The time course of brain damage was not different in the two models, but the time course of brain edema was quite different. Brain edema formation in the photochemical-induced thrombotic occlusion model was significantly greater (P < 0.01) than that in the thermocoagulated occlusion model at all time point studied until 24 h after occlusion of the middle cerebral artery. The present study suggests that the photochemical-induced thrombotic occlusion model has characteristics of both permanent ischemia and ischemia-reperfusion.

Topics: Animals; Brain Edema; Brain Ischemia; Disease Models, Animal; Dizocilpine Maleate; Electrocoagulation; Immunosuppressive Agents; Injections, Intraperitoneal; Injections, Intravenous; Intracranial Embolism and Thrombosis; Male; Neuroprotective Agents; Quinoxalines; Rats; Rats, Sprague-Dawley; Tacrolimus

We have demonstrated that following a single oral dose of L-2-chloropropionic acid (L-CPA) to rats (750 mg/kg; pH 7) there was a marked and widespread loss of granule cells in the cerebellum as assessed by neuropathology by 48 hr. There also appeared to be limited damage to Purkinje cells, whereas stellate, Golgi, and basket cells were not affected by L-CPA administration. The L-CPA-mediated cerebellar neuropathology was accompanied by a significant increase in the cerebellar water content and sodium concentration, 48 hr following L-CPA administration, suggesting an edematous reaction. After 36 hr, the animals displayed marked locomotor dysfunction and had to be terminated at 54 hr due to marked weight loss. We did not observe any neuropathology in forebrain regions nor was the water content in the forebrain significantly different from controls in animals which had been treated with L-CPA. Cerebellar aspartate concentrations were reduced 48 hr following L-CPA administration becoming marked at 54 hr and accompanied by a significant reduction in cerebellar glutamate concentrations. The density of N-methyl-D-aspartate (NMDA) receptors in the granular layer of the cerebellar cortex was also significantly reduced at 48 and 54 hr following L-CPA administration. Prior administration of MK-801 (dizocilpine) (5 mg/kg/i.p.), an irreversible NMDA receptor antagonist, 30 min before an oral dose of L-CPA (750 mg/kg) prevented the loss of both granule and Purkinje cells. There was no abnormal locomotor activity in the L-CPA rats treated with MK-801 except for the first 4 hr following dosing when animals were severely sedated. Animals which received L-CPA plus MK-801 were normal 96 hr post dosing showing that MK-801 did not delay the onset of L-CPA toxicity. There was no alteration in cerebellar water content or sodium concentrations in rats which had been administered MK-801 with L-CPA. The reductions in cerebellar aspartate and glutamate concentrations were totally prevented by administration of MK-801, as was the reduction in L(-)[3H]glutamate binding to cerebellar NMDA receptors. Administration of MK-801 alone (5 mg/kg/i.p.) did not alter the water content, sodium concentrations, aspartate or glutamate concentrations, or the density of NMDA receptors in the cerebellum. In conclusion, we suggest that L-CPA-induced neurotoxicity leading to loss in granule cells and an accompanying cerebellar edema can be prevented by MK-801, suggesting that a subpopulation of NMDA re

Topics: Administration, Oral; Animals; Aspartic Acid; Autoradiography; Brain Edema; Cerebellum; Dizocilpine Maleate; gamma-Aminobutyric Acid; Glutamic Acid; Golgi Apparatus; Hydrocarbons, Chlorinated; Injections, Intraperitoneal; Male; Motor Activity; Neuroprotective Agents; Neurotoxins; Propionates; Purkinje Fibers; Rats; Receptors, N-Methyl-D-Aspartate; Sodium; Stereoisomerism; Synaptic Transmission; Taurine

We assessed the efficacy of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) on brain injury and edema formation after permanent middle cerebral artery occlusion (MCAo) in the rat. Previous studies showed that low amounts of rhIL-1ra injected directly into the brain significantly decreased infarct size after MCAo or excitotoxic injury in rats. Peripheral administration of rhIL-1ra (100 mg/kg sc at 0, 4, 8, 12, and 18 h after MCAo) significantly inhibited infarct size, by 46% (P < 0.05), measured at 24h. This was greater than the effect of MK801 administered immediately after MCAo (4 mg/kg ip, 0 h) which did not significantly reduce infarct size. rhIL-1ra (100 mg/kg also significantly inhibited cerebral edema formation by 49% (p< 0.05 measured 24 h after MCAo, but did not reduce edema formation measured 2 h after MCAo, but did not reduce edema formation measured 2 h after MCAo. Inhibition of infarction by rhIL-1ra was dependent on dose and time of administration. Together the results demonstrate that peripherally administered rhIL-1ra at high doses is able to mimic the efficacy of low dose of rhIL-1ra administered directly into the brain in a rodent model of stroke and that protection observed with rhIL-1ra was better than that offered by MK801 in this model.

Topics: Animals; Blood Glucose; Brain Damage, Chronic; Brain Edema; Brain Ischemia; Cerebral Infarction; Dizocilpine Maleate; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-1; Recombinant Proteins

Diffusion-weighted single voxel experiments conducted at b-values up to 1 x 10(4) smm-2 yielded biexponential signal attenuation curves for both normal and ischemic brain. The relative fractions of the rapidly and slowly decaying components (f1, f2) are f1 = 0.80 +/- 0.02, f2 = 0.17 +/- 0.02 in healthy adult rat brain and f1 = 0.90 +/- 0.02, f2 = 0.11 +/- 0.01 in normal neonatal rat brain, whereas the corresponding values for the postmortem situation are f1 = 0.69 +/- 0.02, f2 = 0.33 +/- 0.02. It is demonstrated that the changes in f1 and f2 occur simultaneously to those in the extracellular and intracellular space fractions (fex, f(in)) during: (i) cell swelling after total circulatory arrest, and (ii) the recovery from N-methyl-D-aspartate induced excitotoxic brain edema evoked by MK-801, as measured by changes in the electrical impedance. Possible reasons for the discrepancy between the estimated magnitude components and the physiological values are presented and evaluated. Implications of the biexponential signal attenuation curves for diffusion-weighted imaging experiments are discussed.

Topics: Age Factors; Animals; Animals, Newborn; Brain Edema; Brain Ischemia; Diffusion; Dizocilpine Maleate; Electric Impedance; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Extracellular Space; Intracellular Fluid; Magnetic Resonance Spectroscopy; N-Methylaspartate; Phantoms, Imaging; Rats; Rats, Wistar; Water

The effects of pre-treatment with the NMDA receptor antagonists MK-801 and D-CPPene on the development of brain oedema were investigated in a rodent model of intracerebral haemorrhage. In acute experiments (4 hour survival) both drugs caused significant hypotension and had significant anaesthetic effects whilst conferring no protection against oedema formation. In chronic experiments (24 hour survival) MK-801 conferred no protection against brain oedema. With D-CPPene marginal protection against cortical oedema may have been conferred but this result should be interpreted with caution.

Topics: Animals; Brain Edema; Cerebral Cortex; Cerebral Hemorrhage; Dizocilpine Maleate; Injections, Intraperitoneal; Male; Piperazines; Premedication; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Time Factors

Brain edema caused by glutamate excitotoxicity was studied in well oxygenated neonatal cerebrocortical brain slices (350 mu thick). Slices exposed to 60 minutes of 2 mM glutamate, with or without glutamate antagonists (dizocilpine, kynurenate, or NBQX), were allowed to recover for 60 minutes. The protocol was identical to that in noninvasive multinuclear NMR spectroscopy studies (31P/1H/19F) of live slices. Percent water and swelling were determined invasively in isolated slices by wet and dry weight measurements before and after glutamate exposure. Edema was detectable within minutes in all experiments with glutamate exposures, but not in untreated control slices. Dizocilpine, kynurenate, and NBQX differently affected swelling, which correlated with PCr and ATP loss in separate NMR studies. Synaptic glutamate receptor activation appears to initiate events causing both edema and energy failure. Multiple glutamate receptor types seem to be involved. No glutamate antagonist provided greater protection against both edema and energy loss than dizocilpine. Dizocilpine might also block voltage-dependent Na+ channels, and provide protection via mechanisms other than NMDA-receptor dependent channel antagonism.

Topics: Animals; Brain Edema; Cerebral Cortex; Culture Techniques; Dizocilpine Maleate; Energy Metabolism; Glutamic Acid; Kynurenic Acid; Magnetic Resonance Spectroscopy; Organ Size; Quinoxalines; Rats; Receptors, AMPA; Receptors, Glutamate; Sodium Channels

This study addresses the issue of endpoint selection in the evaluation of neuroprotective drugs in experimental focal ischaemia. Previous work with the permanent middle cerebral artery (MCA) occlusion model in the rat has demonstrated that the ischaemic lesion does not acquire its final appearance until at least 28 days after the ictus. Therefore, the effect of the NMDA receptor blocker MK-801 (dizocilpine maleate) was evaluated both early (3 days) and late (28 days) after MCA occlusion to determine if the previously reported protective effect of a single post-ischaemic dose of MK-801 found in acute experiments remained after 28 days. Mk-801 (0.5 mg/kg, i.v.) or isotonic saline was randomly given to rats 30 min after MCA occlusion. Infarct volume and volume of ipsilateral and contralateral hemispheres were estimated from camera lucida drawings of 8 defined coronal histological sections of the brain. As expected, a 40% (p < 0.05) reduction of infarct size was found in MK-801 treated rats after 3 days. In animals evaluated 28 days after MCA occlusion, no significant difference in infarct size, total tissue loss (infarct volume+ipsilateral hemisphere atrophy) or remaining non-infarcted tissue (contralateral hemisphere--total tissue loss) was seen between the MK-801 and placebo treated rats. The results suggest that the single dose treatment with MK-801 postponed the evolution of the infarct, which at 3 days after MCA occlusion is still in progress, possibly by ameliorating oedema formation. It remains to be shown if a multiple dose treatment with NMDA receptor antagonists improves the final neuropathological outcome after experimental stroke.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrophy; Brain Edema; Brain Ischemia; Cerebral Cortex; Cerebral Infarction; Dizocilpine Maleate; Dominance, Cerebral; Image Processing, Computer-Assisted; Infusions, Intravenous; Male; Rats; Rats, Sprague-Dawley

The aim of our study was to evaluate whether blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors could reduce brain edema in two experimental models of edema following opening of the blood-brain barrier (BBB). The brain specific gravity was determined 2 h after opening the BBB by a 30-s infusion of protamine sulfate (10 mg in 200 microliters 0.9% NaCl) or arabinose (1.5 or 1.8 mol/L, 0.06 ml.s-1) into the right internal carotid artery. Cisternal CSF was withdrawn for albumin determination before the carotid infusion and before killing 2 h later. After infusion of protamine sulfate or arabinose, CSF albumin increased in all groups. The brain specific gravity was significantly lower in the right than in the left (control) frontal, parietal, and occipital cortex and striatum. NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenxo(F)quinoxaline), an AMPA receptor antagonist, given intravenously 10 min after opening the BBB (5 mg/kg), significantly increased the specific gravity in the treated rats (p < 0.01 for the difference from control rats) without reducing CSF albumin or albumin extravasation in the brain as evaluated with Evans blue. We hypothesize that intracerebral (glial?) AMPA receptors may play a role in brain edema following opening of the BBB.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Dizocilpine Maleate; Evans Blue; Excitatory Amino Acid Antagonists; Injections, Intravenous; Male; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Specific Gravity; Staining and Labeling

We previously described the time course of changes in neurologic status (as indicated by neurologic severity score [NSS]) and cerebral edema (as indicated by brain tissue specific gravity and water content) after closed head trauma in rats. The present study was designed to determine whether head trauma alters the integrity of the blood-brain barrier (BBB), the role of the BBB in edema formation and neurologic outcome, and the effect of MK-801 (a noncompetitive N-methyl-D-aspartate receptor antagonist) on BBB permeability. Rats in which cranial impact was delivered during ether anesthesia (n = 106) were killed at 15 min, 1, 2, 4, 10, and 24 h, and 2, 4, and 7 days. Control rats (n = 12) received no cranial impact. Subsets of head-injured rats killed at 4 and 24 h received MK-801 (3 mg/kg intraperitoneally) 1 h after injury. BBB permeability was assessed with intravenous injection of Evans Blue dye, cerebral edema was assessed by determining brain tissue specific gravity and water content, and neurologic status was assessed using NSS. Tissue extravasation of Evans Blue was maximal in the injured hemisphere 4 h after injury, but a residual BBB permeability defect was still evident as long as 4 days after the insult. In MK-801-treated rats, extravasation of Evans Blue in the injured hemisphere was not significantly different from that in the noninjured hemisphere.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood-Brain Barrier; Brain Edema; Cell Membrane Permeability; Craniocerebral Trauma; Dizocilpine Maleate; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Injury Severity Score; Male; Models, Neurological; Rats; Specific Gravity

Both oxygen free radicals and excitatory amino acids have been implicated as important cellular toxins in ischemic brain. Recent in vitro studies suggest that there may be a mutual interaction between these two mediators. We explored the relation between oxygen free radicals and excitatory amino acids in the development of ischemic brain edema in vivo. Male Sprague-Dawley rats were treated with the free radical scavenger dimethylthiourea 1 hour before ischemia or with the excitotoxin antagonist MK-801 30 minutes before ischemia produced by occlusion of the middle cerebral artery. Groups of seven or eight animals were treated with vehicle, low-dose (375 mg/kg) dimethylthiourea, high-dose (750 mg/kg) dimethylthiourea, low-dose (0.5 mg/kg) MK-801, high-dose (2.0 mg/kg) MK-801, or both high-dose dimethylthiourea and low-dose MK-801. After 4 hours of ischemia, brain water content was determined. In eight vehicle-treated controls, mean +/- SEM water content of tissue in the center of the ischemic zone was 83.29 +/- 0.18%. A significant reduction of brain edema was observed in all drug-treated groups: for example, 50.2% (p less than 0.001) in the high-dose dimethylthiourea group, 53.7% (p less than 0.001) in the low-dose MK-801 group, and 66.4% (p less than 0.001) in the combined dimethylthiourea and MK-801 group. Combined treatment with dimethylthiourea and MK-801 provided no significant additive effect over that resulting from treatment with MK-801 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acids; Animals; Brain; Brain Edema; Brain Ischemia; Dizocilpine Maleate; Drug Interactions; Free Radicals; Male; Neurotoxins; Oxygen; Potassium; Rats; Rats, Inbred Strains; Sodium; Thiourea

Excitotoxin-induced neural tissue damage is mediated through specific receptors. We studied the in vivo effect of two selective N-methyl-D-aspartate receptor antagonists on the compressed spinal cord segments of rats harboring a thoracolumbar epidural tumor. The effect of a single intramuscular treatment with either MK-801 (3 mg/kg) or ketamine (110 mg/kg) given at the onset of paraplegia was evaluated 30 hours later. In saline-treated control animals, significant increases in water content, prostaglandin E2, and 6-keto-prostaglandin F1 alpha were evident. Treatment with either agent resulted in a normal water content in the compressed segments but had no effect on prostaglandin synthesis. Evaluation of the effect of treatment on the course of the disease required dose reduction by 45% for ketamine and by 30% for MK-801, to avoid the excessive sedative effect. Treatment was started at the first appearance of neurological dysfunction (Grade 1) and continued to paraplegia (Grade 5). The mean time interval between Grades 1 and 5 was 2.1 +/- 0.3 days in saline-treated control animals, and it was not significantly altered by either ketamine or MK-801. Our study indicates that in the end stage of epidural compression, when ischemia is present, excitotoxins probably participate in the evolution of a cytotoxic edema. It is suggested that treatment initiated at the onset of paraplegia may still reduce the cytotoxic edema, but its potential clinical value requires further investigations.

Topics: Analysis of Variance; Animals; Brain Edema; Dibenzocycloheptenes; Dizocilpine Maleate; Edema; Histiocytoma, Benign Fibrous; Ketamine; Neurons; Prostaglandins; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Spinal Cord Compression; Spinal Cord Neoplasms

Pharmacological inhibition of excitatory neurotransmission attenuates cell death in models of global and focal ischemia and hypoglycemia, and improves neurological outcome after experimental spinal cord injury. The present study examined the effects of the noncompetitive N-methyl-D-aspartate receptor blocker MK-801 on neurochemical sequelae following experimental fluid-percussion brain injury in the rat. Fifteen minutes after fluid-percussion brain injury (2.8 atmospheres), animals received either MK-801 (1 mg/kg, i.v.) or saline. MK-801 treatment significantly attenuated the development of focal brain edema at the site of injury 48 h after brain injury, significantly reduced the increase in tissue sodium, and prevented the localized decline in total tissue magnesium that was observed in injured tissue of saline-treated animals. Using phosphorus nuclear magnetic resonance spectroscopy, we also observed that MK-801 treatment improved brain metabolic status and promoted a significant recovery of intracellular free magnesium concentrations that fell precipitously after brain injury. These results suggest that excitatory amino acid neurotransmitters may be involved in the pathophysiological sequelae of traumatic brain injury and that noncompetitive N-methyl-D-aspartate receptor antagonists may effectively attenuate some of the potentially deleterious neurochemical sequelae of brain injury.

Topics: Adenosine Triphosphate; Animals; Anticonvulsants; Body Water; Brain; Brain Edema; Brain Injuries; Carbon Dioxide; Cations; Dibenzocycloheptenes; Dizocilpine Maleate; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Oxygen; Phosphates; Phosphocreatine; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Reference Values

The effect of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK801, was studied in a model of closed head injury in rats. Head trauma (HT) was induced over the left cerebral hemisphere by a calibrated weight-drop device. One or 3 h later, MK801 in saline was given i.p. in a single bolus of either 1, 3, or 10 mg/kg. The rats were killed at 4, 24, or 48 h after HT. Cortical tissue samples were taken from the injured zone and from the corresponding region of the contralateral hemisphere and analyzed for specific gravity (SG) by linear gradient columns. The neurological status of the traumatized rats was evaluated by a neurological severity score (NSS) 1 h after trauma and just before death. Pathological evaluation, based on size and severity of the lesion, was performed 24 and 48 h after HT on control and MK801-treated rats. A dose of 3 mg/kg MK801 given 1 h after trauma effectively prevented the reduction in tissue SG only at 24 h. The NSS could not be evaluated at 24 h after trauma because of the sedating effect of the drug. At 48 h posttrauma, however, the drug significantly improved the neurological state of the rats. No significant difference was found in the pathological score between treated and untreated rats. The results demonstrate neuroprotective properties of MK801, as expressed in two different variables--reduced edema formation and improved neurological recovery after HT. These findings support existing evidence that pharmacological intervention with NMDA receptor antagonist after head injury may be of clinical value in the management of head-injured patients.

Topics: Animals; Brain Edema; Brain Injuries; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Rats