dizocilpine-maleate and Heart-Arrest

Motor deficits are present in cardiac arrest survivors and injury to cerebellar Purkinje cells (PCs) likely contribute to impairments in motor coordination and post-hypoxic myoclonus. N-Methyl-D-aspartic acid (NMDA) receptor-mediated excitotoxicity is a well-established mechanism of cell death in several brain regions, but the role of NMDA receptors in PC injury remains understudied. Emerging data in cortical and hippocampal neurons indicate that the GluN2A-containing NMDA receptors signal to improve cell survival and GluN2B-containing receptors contribute to neuronal injury. This study compared neuronal injury in the hippocampal CA1 region to that in PCs and investigated the role of NMDA receptors in PC injury in our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Analysis of cell density demonstrated a 24% loss of PCs within 24 h after 8 min CA/CPR and injury stabilized to 33% by 7 days. The subunit promiscuous NMDA receptor antagonist MK-801 protected both CA1 neurons and PCs from ischemic injury following CA/CPR, demonstrating a role for NMDA receptor activation in injury to both brain regions. In contrast, the GluN2B antagonist, Co 101244, had no effect on PC loss while protecting against injury in the CA1 region. These data indicate that ischemic injury to cerebellar PCs progresses via different cell death mechanisms compared to hippocampal CA1 neurons.

Topics: Animals; Brain Ischemia; CA1 Region, Hippocampal; Calbindins; Cardiopulmonary Resuscitation; Cell Death; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Heart Arrest; Male; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Piperidines; Purkinje Cells; Receptors, N-Methyl-D-Aspartate; Tissue Culture Techniques

Evidence suggests that pre-ischeamic conditioning (PIC) offers protection against a subsequent ischeamic event. Although some brain areas such as the hippocampus have received much attention, the receptor mechanisms of PIC in other brain regions are unknown. We have previously shown that 10 min oxygen and glucose deprivation (OGD) evokes tolerance to a second OGD event in the caudate. Here we further examine the effect of length of conditioning event on the second OGD event. Caudate mouse brain slices were superfused with artificial cerebro-spinal fluid (aCSF) bubbled with 95%O(2)/5%CO(2). OGD was achieved by reducing the aCSF glucose concentration and by bubbling with 95%N(2)/5%CO(2). After approximately 5 min OGD a large dopamine efflux was observed, presumably caused by anoxic depolarisation. On applying a second OGD event, 60 min later, dopamine efflux was delayed and reduced. We first examined the effect of varying the length of the conditioning event from 5 to 40 min and found tolerance to PIC increased with increasing duration of conditioning. We then examined the receptor mechanism(s) underlying PIC. We found that pre-incubation with either MK-801 or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) reduced tolerance to the second OGD event. These data suggest that either N-methyl-D-aspartate (NMDA) or adenosine A(1) receptor activation evokes PIC in the mouse caudate.

Topics: Adenosine A1 Receptor Antagonists; Animals; Brain Ischemia; Caudate Nucleus; Dizocilpine Maleate; Dopamine; Glucose; Heart Arrest; Ischemic Preconditioning; Male; Mice; Mice, Inbred C57BL; Oxygen; Receptor, Adenosine A1; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Tetrazolium Salts; Xanthines

In our exsanguination cardiac arrest (CA) outcome model in dogs we are systematically exploring suspended animation (SA), i.e. preservation of brain and heart immediately after the onset of CA to enable transport and resuscitative surgery during CA, followed by delayed resuscitation. We have shown in dogs that inducing moderate cerebral hypothermia with an aortic arch flush of 500 ml normal saline solution at 4 degrees C, at start of CA 20 min no-flow, leads to normal functional outcome. We hypothesized that, using the same model, but with the saline flush at 24 degrees C inducing minimal cerebral hypothermia (which would be more readily available in the field), adding either fructose-1,6-bisphosphate (FBP, a more efficient energy substrate) or MK-801 (an N-methyl-D-aspartate (NMDA) receptor blocker) would also achieve normal functional outcome. Dogs (range 19-30 kg) were exsanguinated over 5 min to CA of 20 min no-flow, and resuscitated by closed-chest cardiopulmonary bypass (CPB). They received assisted circulation to 2 h, mild systemic hypothermia (34 degrees C) post-CA to 12 h, controlled ventilation to 20 h, and intensive care to 72 h. At CA 2 min, the dogs received an aortic arch flush of 500 ml saline at 24 degrees C by a balloon-tipped catheter, inserted through the femoral artery (control group, n=6). In the FBP group (n=5), FBP (total 1440 or 4090 mg/kg) was given by flush and with reperfusion. In the MK-801 group (n=5), MK-801 (2, 4, or 8 mg/kg) was given by flush and with reperfusion. Outcome was assessed in terms of overall performance categories (OPC 1, normal; 2, moderate disability; 3, severe disability; 4, coma; 5, brain death or death), neurologic deficit scores (NDS 0-10%, normal; 100%, brain death), and brain histologic damage scores (HDS, total HDS 0, no damage; >100, extensive damage; 1064, maximal damage). In the control group, one dog achieved OPC 2, one OPC 3, and four OPC 4; in the FBP group, two dogs achieved OPC 3, and three OPC 4; in the MK-801 group, two dogs achieved OPC 3, and three OPC 4 (P=1.0). Median NDS were 62% (range 8-67) in the control group; 55% (range 34-66) in the FBP group; and 50% (range 26-59) in the MK-801 group (P=0.2). Median total HDS were 130 (range 56-140) in the control group; 96 (range 64-104) in the FBP group; and 80 (range 34-122) in the MK-801 group (P=0.2). There was no difference in regional HDS between groups. We conclude that neither FBP nor MK-801 by aortic arch flush at the start of CA, plus

Topics: Animals; Aorta, Thoracic; Cardiopulmonary Bypass; Cardiopulmonary Resuscitation; Disease Models, Animal; Dizocilpine Maleate; Dogs; Fructose-Bisphosphatase; Heart Arrest; Hemorrhage; Hypothermia, Induced; Hypoxia, Brain; Neuroprotective Agents; Pulmonary Edema; Reperfusion; Treatment Outcome

Numerous studies over the past three decades have used rodent models of cerebral ischemia. To measure the postischemic outcome, the majority of these studies used histopathology as the method of choice both quantitatively and qualitatively. No functional measure of postischemic outcome has been proved to correlate well with the histopathological one. The rat chest compression model of cardiac-arrest-induced global cerebral ischemia was used in the present study. Two separate measures of neuronal damage at 7 days postischemia were performed: (a) histologically, by counting normal pyramidal cell bodies in the mid-CA1 hippocampal region of the rat brain, in hematoxylin-eosin-stained, paraffin-embedded 6-microm sections, and (b) electrophysiologically, by counting the number of 400 microm hippocampal slices in which it was possible to evoke a normal (>/=10 mV) CA1 population spike by orthodromic stimulation of the Schaffer collaterals. The correlation between these two measures was tested in the following groups of rats: (a) control, untreated group, (b) MK-801-treated groups (0.03 to 1.0 mg/kg given i.p. shortly after ischemia), (c) diltiazem-treated (DILT) groups 1.0 to 30 mg/kg, given i.p. shortly after ischemia, and (d) a group treated with a combination of the two drugs together (0.1 mg/kg MK-801+3.0 mg/kg DILT given i.p. shortly after ischemia). The two measures of postischemic outcome were highly correlated in all groups studied. Both MK-801 and DILT exhibited a dose-dependent neuroprotective effect. When administered together, a synergy between the neuroprotective effect of MK-801 and DILT was observed. At the doses used, minimal or no side effects of either MK-801 or DILT were observed.

Topics: Animals; Brain Ischemia; Diltiazem; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Electrophysiology; Excitatory Amino Acid Antagonists; Heart Arrest; Hippocampus; Male; Neuroprotective Agents; Organ Culture Techniques; Pyramidal Cells; Rats; Rats, Long-Evans; Vasodilator Agents

The aim of this study was to investigate whether the neuroprotective properties of magnesium in cerebral ischaemia involve suppression of repetitive tissue depolarizations. Cortical spreading depressions (CSDs), evoked by cortical KCl application, and cardiac arrest-induced anoxic depolarization (AD) were measured by extracellular DC recording on intact rat brain. At 90 min after onset of CSDs saline, MK-801 (3 mg/kg) or MgSO4 (90 mg/kg) was given i.v. Latency time to AD was measured after 4 h. The frequency of CSDs was significantly reduced in animals treated with MgSO4 or MK-801. AD was significantly delayed by MgSO4 but not by MK-801. Our results suggest that suppression of depolarization by magnesium may play a role in its neuroprotective properties in cerebral ischaemia.

Topics: Animals; Body Temperature; Central Nervous System Agents; Cortical Spreading Depression; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Heart Arrest; Hypoxia, Brain; Injections, Intravenous; Magnesium; Magnesium Sulfate; Male; Neuroprotective Agents; Potassium Chloride; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

Anoxic depolarization (AD) and failure of ion homeostasis play an important role in ischemia-induced neuronal injury. In the present study, different drugs with known ion-channel-modulating properties were examined for their ability to interfere with cardiac-arrest-elicited AD and with the changes in the extracellular ion activity in rat brain. Our results indicate that only drugs primarily blocking membrane Na+ permeability (NBQX, R56865, and flunarizine) delayed the occurrence of AD, while compounds affecting cellular Ca2+ load (MK-801 and nimodipine) did not influence the latency time. The ischemia-induced [Na+]e reduction was attenuated by R56865. Blockade of the ATP-sensitive K+ channels with glibenclamide reduced the [K+]e increase upon ischemia, indicating an involvement of the KATP channels in ischemia-induced K+ efflux. The KATP channel opener cromakalim did not affect the AD or the [K+]e concentration. The ischemia-induced rapid decline of extracellular calcium was attenuated by receptor-operated Ca2+ channel blockers MK-801 and NBQX, but not by the voltage-operated Ca2+ channel blocker nimodipine, R56865, and flunarizine.

Topics: Adenosine Triphosphate; Animals; Benzothiazoles; Calcium; Dizocilpine Maleate; Flunarizine; Glyburide; Heart Arrest; Hypoxia; Ion Channels; Male; Nimodipine; Piperidines; Potassium; Potassium Channels; Quinoxalines; Rats; Rats, Wistar; Sodium; Thiazoles

The objective of this study was to explore how alterations in tissue pH during ischemia influence cell calcium uptake, as this is reflected in the extracellular calcium concentration (Ca2+e). Variations in pH were achieved by making animals hypo-, normo- or hyperglycemic prior to cardiac arrest ischemia or by increasing preischemic PCO2 in normoglycemic animals. For comparison, the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) was given prior to induction of ischemia. In some experiments the effect of acidosis on K+ efflux and Na+ influx were studied as well. In hypoglycemic subjects, the reduction of Ca2+e during ischemia was very rapid, 90% of the reduction occurring within 4.7 s. Normoglycemic animals showed a slower rate of reduction of Ca2+e. Hyperglycemic animals displayed an even slower rate of reduction and a biphasic response in which the initial, faster influx of Ca2+ was followed by a conspicuously slow one. This second phase led to a very gradual decrease in Ca2+e, a stable level being reached first after 6-7 min. This marked delay in calcium influx during ischemia was very similar in hypercapnic animals, who showed an extracellular pH during ischemia as low as hyperglycemic subjects. The effect of acidosis was duplicated by MK-801, suggesting that low pH reduces calcium influx by blocking NMDA-gated ion channels.

Topics: Animals; Blood Glucose; Brain; Brain Ischemia; Calcium; Carbon Dioxide; Cerebral Cortex; Dizocilpine Maleate; Heart Arrest; Hydrogen-Ion Concentration; Hyperglycemia; Hypoglycemia; Male; Parietal Lobe; Potassium; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Sodium

We investigated the effects of cardiac arrest and resuscitation on (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine meleate (MK-801) pharmacokinetics. The clearance of MK-801 in control animals was 108 +/- 9 mL.kg.min while its apparent volume of distribution was 12.6 +/- 0.7 L/kg. The half-life of the distribution phase was 4.9 +/- 1.2 min while that of the elimination phase was 87 +/- 8 min. Transient circulatory arrest decreased the overall clearance of MK-801 by 38% with no effect on the apparent volume of distribution. The distribution half-life was not affected although the initial distribution was increased 46%; the half-life of elimination was increased by 58%. Serum levels of transaminases in arrested animals were significantly elevated (258-322%) while blood urea nitrogen, creatinine, and creatine kinase were minimally affected, suggesting that the reduced clearance of MK-801 might be secondary to hepatic ischemic damage. Post-ischemic alterations in hemodynamics resulting in lowering and/or redistribution of cardiac output may also be responsible for the reduced clearance of MK-801 as the hemodynamic response to MK-801 in the post-ischemic animals was quite different from that in the controls. We conclude that transient cardiac arrest significantly alters the pharmacokinetics of MK-801 and that this must be taken into consideration when using this or other drugs to treat ischemic injury.

Topics: Animals; Blood Urea Nitrogen; Cardiopulmonary Resuscitation; Coronary Disease; Creatine Kinase; Creatinine; Dizocilpine Maleate; Half-Life; Heart Arrest; Hemodynamics; Male; Rats; Rats, Inbred Strains; Transaminases

Excitatory amino acids accumulating in the brain during ischemia may cause selective neuronal damage postischemia. This hypothesis was tested in a series of studies using MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, in a reproducible outcome model of prolonged cardiac arrest in dogs. After normothermic ventricular fibrillation cardiac arrest, the dogs were resuscitated with closed-chest femoral veno-arterial cardiopulmonary bypass. At 4 h they were separated from bypass, ventilation was controlled for 20 h, and intensive care was continued to 96 h. In Study I, ventricular fibrilation cardiac arrest (no-flow) was 17 min; starting immediately with reperfusion, MK-801 1200 mg/kg (n = 5) or an equal volume of placebo (n = 5) was infused over 12 h in blinded, randomized fashion. In Study II, the duration of the no-flow period was reduced to 15 min, and MK-801 2400 mg.kg-1 (n = 4) or placebo (n = 4) was infused. In Study III, no-flow lasted for 15 min, and MK-801 2400 mg/kg was started 30 min before ventricular fibrillation (n = 4); comparison was with Study II controls. In all three studies, MK-801 plasma concentrations peaked at greater than 50 ng/ml and were 15-30 ng/ml over 12 h. All 22 dogs of experiments within protocol survived with severe brain damage. MK-801 delayed return of pupillary reactivity, EEG activity, consciousness, and respiration, necessitating longer periods of controlled ventilation. Neurologic deficit scores, overall performance categories, and brain and heart morphologic damage scores at 96 h did not differ between placebo and MK-801 pretreatment or post-treatment groups. These negative outcome results after prolonged cardiac arrest do not negate the hyperexcitability hypothesis of selective vulnerability, but suggest the existance of additional mechanisms of secondary brain damage.

Topics: Animals; Anticonvulsants; Dibenzocycloheptenes; Dizocilpine Maleate; Dogs; Heart Arrest; Male; Prognosis; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Resuscitation; Time Factors

The excitatory amino antagonist MK-801 was administered to cats following resuscitation from cardiac arrest to evaluate its effect on neurologic and neuropathologic outcome in a clinically relevant model of complete cerebral ischemia. In 29 cats studied, cardiac arrest (ventricular fibrillation) was maintained for 18 min and resuscitation was successfully performed in 21 cats. Four animals underwent a sham arrest. MK-801 or placebo was administered in a blinded, randomized manner. Beginning at 5 min post resuscitation (PR), MK-801 330 micrograms/kg over 2 min followed by 73 micrograms/kg/h for 10 h or the same volume of placebo was administered. Resuscitated animals remained paralyzed and sedated in an intensive care setting for 24-30 h PR. Neurologic examinations were performed at 2, 4, and 7 days PR by observers blinded to the treatment groups. Seventeen cats were entered into data analysis (nine MK-801-treated and eight placebo-treated). MK-801-treated animals had a significantly greater neurologic deficit score (NDS) rank (0 = normal, 100 = brain death) 2 days PR (mean rank 12.1 vs. 5.6; p = 0.008). This difference is most likely due to ongoing sedative actions of MK-801. There were no significant differences in NDS rank at 4 (10.3, MK-801 vs. 7.5, placebo) and 7 (9.6, MK-801 vs. 8.3, placebo) days PR. There were no significant differences in frontal cortex, hippocampus, occipital cortex, or cerebellar neuropathology between groups. Sham-arrested cats had normal neurologic and neuropathologic evaluations. In the circumstance of complete cerebral ischemia as employed in the current study, MK-801 had no beneficial effect upon neurologic or neuropathologic outcome.

Topics: Animals; Anticonvulsants; Behavior, Animal; Blood Pressure; Brain; Cats; Dibenzocycloheptenes; Dizocilpine Maleate; Gait; Heart Arrest; Heart Rate; Muscle Tonus; Nervous System; Nervous System Physiological Phenomena; Organ Specificity; Reference Values; Resuscitation