dizocilpine-maleate and Brain-Damage--Chronic

The relationship of thiamine deficiency to Wernicke's encephalopathy has been well established. The biochemical bases and physiologic mechanisms responsible for the pathologic changes and their selective distribution within the brain remain controversial. The present paper reviews recent biochemical, histopathological and pharmacological evidence of a glutamate-mediated excitotoxic mechanism of neuronal loss in pyrithiamine-induced thiamine deficiency (PTD), a rat model of Wernicke's encephalopathy. A mechanistic model involving the unique combination of thiamine deficiency-induced impairment of energy metabolism, increased release of histamine, and multidirectional glutamate inputs is presented to explain the selective vulnerability of thalamic nuclei to excitotoxic lesions in the PTD model.

Topics: Animals; Brain Damage, Chronic; Diencephalon; Disease Models, Animal; Dizocilpine Maleate; Energy Metabolism; Histamine; Magnesium; Mammillary Bodies; Rats; Thalamus; Thiamine Deficiency; Wernicke Encephalopathy

Delayed selective nerve cell death as seen in the hippocampal CA1 area of gerbils after transient forebrain ischemia goes along with neuronal hyperactivity and an early demonstrable accumulation of calcium in circumscribed groups of nerve cells. Application of NMDA receptor-blockers such as MK 801 prevents neuronal damage. This suggests the involvement of NMDA receptors which are operated by glutamate and known to mediate a special Ca2+ influx required also for establishing sustained enhancement of synaptic efficacy. Thus, the excessive postischemic accumulation of calcium, thought to be instrumental in the generation of nerve cell death, seems to result from turning on a dangerous, but primarily physiological mechanism which ran out of control. We studied the endogenous control mechanisms by which the firing pattern of nerve cells and the initiation of NMDA receptor-mediated neuronal Ca2+ influx are controlled focusing in particular on the role of adenosine. This nucleoside is released from nerve- and glial cells in larger amounts after ischemia. It counteracts at increased extracellular concentration the generation of burst discharges, an effect which is ascribed to a modulation of the dendritic membrane properties. Removal of a possible action of endogenous adenosine by receptor antagonists such as theophylline was found to enhance postischemic nerve cell death. This together with other reported experimental evidences points to a protective action of this nucleoside in the brain. The presumed mechanisms by which this effect is achieved were studied in a rat hippocampal slice using ion selective electrodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Animals; Brain Damage, Chronic; Brain Ischemia; Calcium; Culture Techniques; Dizocilpine Maleate; Epilepsy, Post-Traumatic; Gerbillinae; Hippocampus; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission

Excitotoxic mechanisms due to overactivity of the amino acid neurotransmitters glutamate and aspartate maybe responsible for brain damage after injury. In this review we examine ischaemia and shear injury, which are relevant to human head injury. The opportunities for treatment using glutamate antagonist drugs are discussed.

Topics: Animals; Brain Damage, Chronic; Brain Injuries; Brain Ischemia; Central Nervous System Agents; Dizocilpine Maleate; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Humans; Receptors, N-Methyl-D-Aspartate; Retrograde Degeneration

Ischemic damage, chiefly of the focal type, and axonal disruption (diffuse axonal injury) are the major factors causing brain damage after human head injury. About one third of this damage may be delayed hours or days after the injury. Evidence from four animal models, each relevant to different aspects of human head injury, has shown that excitatory amino acid-induced changes are responsible for a proportion of the posttraumatic sequelae and that these effects can be blocked by EAA antagonists. This evidence is reviewed, and the implications for the conduct of human trials with EAA antagonists are discussed.

Topics: Animals; Brain Damage, Chronic; Brain Injuries; Brain Ischemia; Central Nervous System Depressants; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Ischemic Attack, Transient; Spinal Cord Injuries

Excess activation of ionotropic glutamate receptors and iron is believed to contribute to free radical production and neuronal death following hypoxic ischemia. We examined the possibility that both NMDA receptor activation and iron overload determine spatial and temporal patterns of free radical production after transient middle cerebral artery occlusion (tMCAO) in male Sprague-Dawley rats. Mitochondrial free radical (MFR) levels were maximally increased in neurons in the core at 1 h and 24 h after tMCAO. Early MFR production was blocked by administration of MK-801, an NMDA receptor antagonist, but not deferoxamine, an iron chelator. Neither MK-801 nor deferoxamine attenuated late MFR production in the core. Increased MFRs were observed in penumbral neurons within 6 h and gradually increased over 24 h after tMCAO. Slowly-evolving MFRs in the core and penumbra were accompanied by iron overload. Deferoxamine blocked iron overload but reduced MFR production only in the penumbra. Combined MK-801/deferoxamine reduced late MFR production in both core and penumbra in an additive manner. Combination therapy significantly ameliorated infarction compared with monotherapy. These findings suggest that the NMDA receptor activation and iron overload mediate late MFR production and infarction after tMCAO.

Topics: Animals; Brain Damage, Chronic; Deferoxamine; Disease Models, Animal; Dizocilpine Maleate; Free Radicals; Infarction, Middle Cerebral Artery; Iron; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

We have previously shown that P7 rat pups injected with the N-methyl-d-aspartate receptor (NMDAR) blocker MK801 displayed robust apoptotic injury within hours after injection. Further studies from our lab suggest that loss of calcium cannot be compensated for when vulnerable neurons lack calcium buffering capabilities. Thus, to elevate calcium in these neurons prior to MK801 exposure, we injected P7 rats with the calcium channel agonist BayK 8644. Whereas BayK 8644 did not induce apoptosis by itself, it was found to block MK801-induced injury in a dose-dependent manner. Reversal of MK801 toxicity was complete in the caudate-putamen, partial in the somatosensory cortex but was not observed in the retrosplenial cortex. These results suggest that postnatal brain injury resulting from agents that block the NMDAR, which include commonly used anesthetics as well as drugs of abuse, may be prevented in vulnerable neurons by compensatory increases in calcium prior to exposure to these antagonists.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Animals, Newborn; Apoptosis; Brain; Brain Damage, Chronic; Calcium Channel Agonists; Calcium Channels; Calcium Signaling; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Neostriatum; Nerve Degeneration; Neurons; Rats; Receptors, N-Methyl-D-Aspartate; Somatosensory Cortex

Topics: Animals; Brain Damage, Chronic; Cerebral Hemorrhage; Dizocilpine Maleate; Glucose; Neuroprotective Agents; Norepinephrine; Rats

The polyamine sites on the NMDA receptor complex offer a therapeutic target for focal ischaemia, potentially devoid of most side effects associated with NMDA antagonists. In this study, we investigated the effect of a novel polyamine antagonist, N(1)-dansyl-spermine (0.5-10 mg kg(-1)) in a permanent focal cerebral ischaemia model in mice, and compared its effect to that of MK-801 (0.3-3 mg kg(-1)) following administration 30 min prior to ischaemia. A battery of histological and behavioural tests was employed following permanent middle cerebral artery occlusion to assess any neuroprotective effect. Following middle cerebral artery occlusion, N(1)-dansyl-spermine (1-5 mg kg(-1)) and MK-801 (1 or 3 mg kg(-1)) caused a comparable and significant reduction in the percentage hemisphere lesion volume. Similarly, both drugs significantly reduced oedema and neurological deficit score to a similar extent. Locomotor activity in MCAO mice was not significantly improved by MK-801 or N(1)-dansyl-spermine, although N(1)-dansyl-spermine induced a trend towards significant improvement. Significant improvement in rotarod performance was observed at neuroprotective doses with both drugs. Upon comparison of the profile of effects, N(1)-dansyl-spermine at least matched the effectiveness of MK-801 as a neuroprotective agent in this model. In addition, in sham-operated control mice, N(1)-dansyl-spermine was well tolerated, in contrast to the pronounced adverse effects of MK-801 on locomotor activity and rotarod performance. In conclusion, this study has shown that N(1)-dansyl-spermine is as effective a neuroprotective drug as MK-801 in this model. Moreover, in contrast to MK-801, N(1)-dansyl-spermine could be a promising therapeutic candidate for stroke as it is well tolerated at neuroprotective doses in sham-operated animals.

Topics: Analysis of Variance; Animals; Behavior, Animal; Brain Damage, Chronic; Brain Ischemia; Dansyl Compounds; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Mice; Motor Activity; Neuroprotective Agents; Polyamines; Receptors, N-Methyl-D-Aspartate; Rotarod Performance Test; Spermine

Severe hyperbilirubinemia in neonates with prematurity and/or systemic illnesses such as hemolytic disease, acidosis, and hypoxemia enhances their risk for developing cerebral palsy, paralysis of ocular upgaze, and deafness. This neurologic syndrome has been associated with selective neuronal vulnerability in the basal ganglia, certain brainstem nuclei, and Purkinje cells. However, the mechanism by which bilirubin damages neurons remains unclear. In these studies, we found that intracerebral injection of N-methyl-D-aspartate (NMDA), an excitotoxic analogue of glutamate, caused greater injury in jaundiced 7-day-old Gunn (jj) rat pups than in nonjaundiced heterozygous (Nj) littermate controls. NMDA injection caused even greater injury when protein-bound bilirubin was displaced with the sulfonamide drug sulfadimethoxine in jaundiced homozygous pups. In additional experiments, the acute signs of bilirubin-mediated neuronal injury, induced in homozygous (jj) Gunn rats by treatment with sulfonamide, were reduced by concurrent treatment with the NMDA-type glutamate channel antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine (MK-801, dizocilpine). The results suggest that bilirubin may cause encephalopathy and neuronal injury, at least in part, through an NMDA receptor-mediated excitotoxic mechanism. This conclusion is consistent with clinical observations that bilirubin encephalopathy is synergistically worsened by hypoxemia, which also shares an excitotoxic mechanism of neuronal injury.

Topics: Animals; Apoptosis; Bilirubin; Brain Damage, Chronic; Disease Models, Animal; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Genotype; Glucuronosyltransferase; Injections; Kernicterus; N-Methylaspartate; Neurotoxins; Purkinje Cells; Rats; Rats, Gunn; Receptors, Glutamate; Sulfadimethoxine

In acute brain injury syndromes, the potent N-methyl-D-aspartate (NMDA) antagonist, MK-801, can prevent neuronal degeneration, and the general anesthetics, isoflurane and propofol, may also provide neuroprotective benefits. An obstacle to the use of NMDA antagonists for neuroprotective purposes is that they can cause a neurotoxic vacuole reaction in cerebrocortical neurons. This study demonstrates the ability of isoflurane and propofol to prevent the neurotoxic vacuole reaction induced by MK-801. Low sedative doses of inhaled isoflurane (1%) or intravenous (i.v.) propofol (7.5 mg/kg/h) were as effective as higher general anesthetic doses. Thus, in the clinical management of acute brain injury conditions such as stroke and brain trauma, administration of one of these anesthetic agents together with an NMDA antagonist may be an excellent formula for obtaining optimal neuroprotection while eliminating serious side effects.

Topics: Anesthetics, Inhalation; Animals; Brain Damage, Chronic; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Gyrus Cinguli; Hallucinogens; Isoflurane; Nerve Degeneration; Neuroprotective Agents; Propofol; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

1. The authors examined the anticonvulsant effects of MK-801 on the pilocarpine-induced seizure model. Intraperitoneal injection of pilocarpine (400 mg/kg) induced tonic and clonic seizure. Scopolamine (10 mg/kg) and pentobarbital (5 mg/kg) prevented development of pilocarpine-induced behavioral seizure but MK-801 (0.5 mg/kg) did not. 2. An electrical seizure measured with hippocampal EEG appeared in the pilocarpine-treated group. Scopolamine and pentobarbital blocked the pilocarpine-induced electrographic seizure, MK-801 treatment augmented the electrographic seizure induced by pilocarpine. 3. Brain damage was assessed by examining the hippocampus microscopically. Pilocarpine produced neuronal death in the hippocampus, which showed pyknotic changes. Pentobarbital, scopolamine and MK-801 protected the brain damage by pilocarpine, though in the MK-801-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that status epilepticus induced by pilocarpine is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause brain damage through an excitatory NMDA receptor-mediated mechanism.

Topics: Animals; Brain Damage, Chronic; Dizocilpine Maleate; Male; Pilocarpine; Rats; Rats, Sprague-Dawley; Seizures

We tested the hypothesis that the administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid) (NPC 17742) or cis-4-(phosphonomethyl) piperidine-2-carboxylic acid (CGS 19755) or the noncompetitive NMDA receptor antagonist dizocilpine (MK-801), at the appropriate doses, would all have efficacy in decreasing early postischemic brain injury in a feline model of transient focal ischemia.. Prospective, randomized, controlled animal trial.. University research laboratory.. Forty mixed-breed cats.. Halothane-anesthetized cats underwent 90 mins of left middle cerebral artery occlusion plus 4 hrs of reperfusion. At 75 mins of ischemia, control cats received intravenous saline (n = 10). Experimental cats (n = 10 in each group) were treated with NPC 17742 (5 mg/kg bolus and 2.5 mg/kg/hr throughout reperfusion), MK-801 (5 mg/kg intravenous bolus), or CGS 19755 (40 mg/kg intravenous bolus) in a randomized fashion.. Microsphere-determined blood flow to the ipsilateral inferior temporal cortex and caudate nucleus decreased to the same extent during ischemia, and recovered to the same extent during early reperfusion, in the four groups. Triphenyltetrazolium-determined injury volume of the ipsilateral caudate nucleus in cats treated with NPC 17742 (105 +/- 25 [SEM] mm3), MK-801 (97 +/- 22 mm3), and CGS 19755 (97 +/- 13 mm3) was less than in control cats (198 +/- 21 mm3). Hemisphere injury volumes with NPC 17742 (1209 +/- 405 mm3) and MK-801 (1338 +/- 395 mm3) were less than that value in controls (2193 +/- 372 mm3), whereas injury volume with CGS 19755 (1553 +/- 519 mm3) treatment did not attain significance (p < .09).. NMDA receptor activation during reperfusion may contribute to the progression of injury in ischemic border regions after 90 mins of transient focal ischemia in the cat. At the doses chosen, there appear to be no major differences in therapeutic efficacy for competitive and noncompetitive NMDA receptor antagonists.

Topics: Amino Acids; Animals; Brain; Brain Damage, Chronic; Cats; Cerebrovascular Circulation; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Ischemic Attack, Transient; Male; Neuroprotective Agents; Pipecolic Acids; Prospective Studies; Receptors, N-Methyl-D-Aspartate

The NMDA receptor subtype is the major excitatory mediator for glutamate neurotoxicity. To assess its participation in the noxious effects of postnatal hypoxia, we have characterized the binding of the ionophoric marker of NMDA receptor, dizocilpine (MK-801). Binding of (+)-3-[125I]MK-801 to NMDA brain receptors under nonequilibrium conditions was quantified by in vitro autoradiography in rats exposed to hypoxia induced by 93% N2/6.5% O2 exposure for 70 min on Postnatal Day 4. Acute and long-lasting effects were investigated at 4 h after injury and on Postnatal Day 40. At the acute stage, a transient decrease in binding was found in several specific brain areas, hypothalamus, amygdaloid nuclei, entorhinal cortex, perirhinal cortex, and hippocampus, and no differences were found in temporal cortex, thalamus, and geniculate nucleus, when compared to sham-treated animals. At this early age, there was no increase of binding when slices from both groups were incubated in the presence of glutamate and glycine (Glu/Gly), positive allosteric modulators of MK-801 binding. In the 40-day-old brains, the binding to the NMDA receptors of hypoxiatreated animals was not different with respect to controls in most of the areas studied, but the Glu/Gly stimulation of binding in hypoxic rats showed a reduced, or absent, response to the allosteric modulators. In contrast, control rats showed a remarkable increase of the specific binding induced by the presence of the modulators in the incubation buffer. Binding of (+)-3-[125I]MK-801 was also performed at a higher concentration to clarify whether the altered response to Glu/Gly may be due to differences in the number of channels; however, the density of NMDA receptors at this concentration was similar in both control and hypoxia-treated rats. We conclude that the effect of exposure of newborn rats to hypoxia can generate acute and long-lasting effects on the NMDA receptor. The deleterious action of this kind of noxa on the CNS could be exerted by interference with normal glutamatergic transmission and hence over normal growth and development.

Topics: Acute Disease; Animals; Animals, Newborn; Brain Chemistry; Brain Damage, Chronic; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Hypoxia; Hypoxia, Brain; Organ Specificity; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Time Factors; Up-Regulation

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

Glutamate receptors are numerous on the ischemia vulnerable CA-1 pyramidal cells. Postischemic use of the AMPA antagonist NBQX has shown up to 80% protection against cell death. Three aspects of this were studied: In the first study, male Wistar rats were given NBQX (30 mg/kg x 3) either 20 hours or immediately (0 h) before 12 min of 4-vessel occlusion with hypotension. After six days of reperfusion comparison with an untreated group showed almost full protection in the 0 h group (4% cell loss, p < 0.001) but only slight protection in the 20 h group (62% cell loss, p < 0.05). After 12 min of ischemia in the present model, eosinophilic CA-1 cells are seen from day 2 on. Since there could be a late, deleterious calcium influx via NMDA receptors, one group of ischemic rats was given MK-801 (5 mg/kg i.p.) 24 hours after ischemia. However, quantitation 6 days later of remaining CA-1 cells showed no protection. In the third study referred here, two groups of ischemic rats were given NBQX (30 mg/kg x 3) immediately after ischemia. The groups survive for six and 21 days, respectively. Counting of CA-1 pyramidal cells showed an equal, significant protection in both groups (approx 20% cell loss).

Topics: Animals; Brain Damage, Chronic; Brain Ischemia; Brain Mapping; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Male; Neurons; Premedication; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

In a model of perinatal hypoxic-ischemic brain damage, we examined the neuroprotective efficacy of posttreatment with the NMDA receptor antagonist MK-801 and the AMPA receptor antagonist NBQX. Unilateral brain damage developed in 95% of rat pups subjected to hypoxia-ischemia with a 27.8 +/- 1.2% weight deficit of the damaged hemisphere. MK-801 in doses of 0.3 and 0.5 mg/kg i.p. reduced the brain damage by 61% (p < 0.001) and 43% (p < 0.001), respectively. A higher dose of MK-801 (0.75 mg/kg) did not offer neuroprotection. Treatment with NBQX (40 mg/kg) reduced the hemispheric lesion by 28% (p < 0.05). In conclusion, posttreatment with both NBQX and low doses of MK-801 reduced perinatal brain damage. The NMDA receptor antagonist offered stronger neuroprotection which is in agreement with a proposed NMDA receptor hyperactivity around postnatal day 7 in rats.

Topics: Animals; Animals, Newborn; Brain Damage, Chronic; Brain Ischemia; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Hypoxia, Brain; Injections, Intraperitoneal; Male; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Severity of Illness Index; Treatment Outcome

Quisqualate (Quis) and other excitotoxins such as ibotenate and N-methyl aspartate, have been used to destroy neurons in the area of the nucleus basalis magnocellularis (NBM) in order to study the relationship between loss of cholinergic neurons in the basal forebrain and various behavioral deficits, including learning and memory impairments. The results of several studies suggest that although Quis NBM lesions may produce greater depletions in cortical choline acetyltransferase levels than ibotenate lesions, the learning/memory deficits tend to be milder following Quis lesions. In these studies, it was often assumed that the lesions induced by Quis were restricted to the local vicinity of the injection. However, in the present study, we found that an injection of Quis into the NBM/substantia inominata (SI) region often induces limbic seizures and disseminated brain damage. Specifically, we found that an injection of Quis into the NBM/SI area of female rats at a dose (120 nmol) used by others in previous behavioral studies produced massive damage in areas distant from the lesion site, particularly in the amygdala and piriform cortex. This disseminated damage occurred in 50% of the rats treated with Quis, was typically more severe than damage at the injection site, and was often accompanied by equally severe "mirror" lesions in the contralateral amygdala and piriform cortex. Injecting rats with MK-801 (1 mg/kg) 30 min before the Quis injection protected against the disseminated damage. These data underscore the need for careful histological evaluation of excitotoxic lesions and for caution in interpreting the relationship between altered transmitter markers and learning/memory impairment seen following these lesions.

Topics: Amygdala; Animals; Brain Damage, Chronic; Dizocilpine Maleate; Female; Limbic System; Motor Activity; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Seizures; Stereotaxic Techniques; Substantia Innominata

Excessive activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been implicated in the sequence of neurochemical events in cerebral ischaemia that results in irreversible neuronal damage. The effects of the NMDA antagonist MK-801 upon the amount of ischaemic brain damage has been assessed quantitatively in a cat and in a rat model of focal cerebral ischaemia. In chloralose-anaesthetised cats, focal cerebral ischaemia was produced by permanent occlusion of one middle cerebral artery (MCA) and the animal sacrificed 6 hours later. Pretreatment with the non-competitive NMDA antagonist, MK-801 (5 mg/kg, i.v.) reduced significantly the volume of ischaemic damage in the cerebral cortex by 57% compared to vehicle-treated cats. A similar degree of neuroprotection could be demonstrated in the cat MCA occlusion model if treatment with MK-801 was initiated 2 hours after the induction of ischaemia. In halothane-anaesthetised rats, focal cerebral ischaemia was produced by permanent MCA occlusion and the animals sacrificed 3 hours later. Pretreatment with MK-801 (0.5 mg/kg, i.v.) reduced the volume of ischaemic damage in the cerebral cortex by 38%; treatment with MK-801 initiated 30 minutes after MCA occlusion was equally effective in reducing cortical damage. In contrast to calcium entry blockers such as nimodipine in the rat MCA occlusion model, the improved histopathological outcome with MK-801 is not associated with improvement in cerebral tissue perfusion to the ischaemic tissue. The increasing evidence that NMDA receptor antagonists are beneficial in experimental focal cerebral ischaemia is reviewed.

Topics: Animals; Brain Damage, Chronic; Brain Ischemia; Cats; Caudate Nucleus; Cerebral Cortex; Cerebral Infarction; Dizocilpine Maleate; Dominance, Cerebral; Male; Nimodipine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

The effect of treatment with the potent, non-competitive NMDA receptor-channel antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5,10-imine maleate (MK-801) on ischemia-induced brain damage was studied in a well-characterized model of focal neocortical infarction in spontaneously hypertensive rats. Anesthesia exposure was minimized to the surgical procedure and the infarcts were allowed to mature over a 24-h period. Pretreatment with 5 mg/kg i.p. MK-801 (n = 11 control, n = 12 treated animals) 30 min before induction of focal cerebral ischemia had no statistically significant influence on infarct volumes. However, pre- and post-treatment with MK-801 5 mg/kg i.p. 30 min before induction of ischemia and 2.5 mg/kg each at 8 and 16 h after onset of ischemia, reduced infarct volumes in two separate studies by 29% (investigator J.T., n = 5 control and n = 7 treated animals) and 20% (investigator U.D., n = 8 control and n = 8 treated animals), respectively. The combined reduction in infarct volume in MK-801-treated animals for both investigators was 23% (P = 0.016, ANOVA). The findings indicate a smaller neuroprotective effect of MK-801 in spontaneously hypertensive rats subjected to focal ischemia than in previous reports using normotensive animals.

Topics: Animals; Behavior, Animal; Brain Damage, Chronic; Cerebral Cortex; Cerebral Infarction; Dizocilpine Maleate; Drug Administration Schedule; Hypertension; Ischemic Attack, Transient; Male; Monitoring, Physiologic; Rats; Rats, Inbred SHR; Receptors, N-Methyl-D-Aspartate

We evaluated the neuroprotective effect of MK-801, a noncompetitive, selective N-methyl-D-aspartate receptor antagonist, in a neonatal hypoxic-ischemic animal model. Seven-day-old rats underwent bilateral ligation of the carotid arteries followed by exposure to an 8% oxygen atmosphere for 1 hr. We sacrificed the animals 72 hrs later and assessed the hypoxic-ischemic brain damage histologically. MK-801 (10 mg/kg), administered IP 0.5 hr before the hypoxia, completely prevented hypoxic-ischemic infarction in cerebral cortex, while treatment immediately and 1 hr after the end of the hypoxia resulted in 76% and 52% reduction in the infarcted area, respectively. MK-801, given 0.5 hr before and immediately after the insult, reduced striatal damage and, given 0.5 hr before, attenuated neuronal necrosis in hippocampal regions. These results show that in neonates MK-801 is neuroprotective even when administered up to 1 hr after the end of a hypoxic-ischemic insult.

Topics: Animals; Animals, Newborn; Brain; Brain Damage, Chronic; Brain Ischemia; Dibenzocycloheptenes; Dizocilpine Maleate; Hypoxia; Rats; Rats, Inbred Strains