dizocilpine-maleate and Magnesium-Deficiency

Elevated plasma levels of the neuropeptide substance P (SP) precede the perivascular inflammatory infiltrate seen in hearts of Mg(2+)-deficient (MgD) animals. The N-methyl-d-aspartate (NMDA) receptor is found in neurons, and activation of this receptor participates in SP release; under normal circumstances, this release can be blocked by Mg(2+). Therefore, we reasoned that blockade of the NMDA receptor with dizolcipine maleate (a noncompetitive NMDA receptor antagonist) would prevent SP release from C-fibers due to MgD. In this study, animals were implanted with slow-release pellets containing dizolcipine or placebo and were fed with diet sufficient in Mg(2+) or deficient with only 9% of USDA-recommended Mg(2+). SP immunostaining of dorsal root ganglia showed a time-dependent depletion of SP in the MgD animals, with a dramatic decrease of SP by week 2; this depletion was prevented by pretreatment with dizolcipine maleate. The significant increase in plasma prostaglandin E(2) levels during MgD was prevented by dizolcipine, and the loss of total red blood cell glutathione content was significantly attenuated by NMDA blockade after 3 weeks of MgD (p < 0.01 versus controls). Immunohistochemical and Western blot analyses of ventricular tissue demonstrated that NMDA receptor blockade abolished MgD-related increase of endothelium adhesion molecule CD54 (weeks 1 and 2; p < 0.05), and of monocyte/macrophage surface protein CD11b expression (week 3; p < 0.05). We conclude that NMDA receptor blockade with dizolcipine maleate prevented SP depletion and reduced perivascular inflammatory infiltrates, thus decreasing cardiac injury due to Mg(2+) deficiency.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluorescent Antibody Technique; Heart Diseases; Inflammation; Intercellular Adhesion Molecule-1; Magnesium Deficiency; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Stress, Physiological; Substance P

The aim of this study was to determine the changes of the nociceptive thresholds in response to an acute mechanical stimulus (paw pressure) in magnesium (Mg)-deficient rats, and the involvement of the NMDA receptor in these changes. Changes in vocalization thresholds was determined after 7 days of feeding with a Mg-depleted diet. Compared with the control group, Mg-deficient rats showed a significant decrease in the vocalization thresholds (-35.8 +/- 2.5%, p < 0.001) reflecting hyperalgesia. In Mg-deprived rats, three doses (0.06, 0.12 and 0.24 mg/kg s.c.) of dizocilpine (MK801), a non-competitive NMDA receptor antagonist, significantly reversed the hyperalgesia in a dose-dependent manner for at least 48 h. No effect of MK801 was observed in the control group. These data provide evidence that Mg deficiency could constitute a new model of hyperalgesia involving NMDA receptors.

Topics: Analysis of Variance; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hyperalgesia; Magnesium Deficiency; Male; Pain Threshold; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Stress, Mechanical

The behavioral changes associated with seizures induced by auditory stimulation in magnesium (Mg)-deficient rats originate in deep brain structures and secondarily project to neocortex. In the present study, we examined the roles of N-methyl-D-aspartate (NMDA) receptors in this seizure model. The intraperitoneal administration of the competitive NMDA receptor blocker DL-2-amino-7-phosphonoheptanoic acid (36 and 72 mg/kg) and the non-competitive NMDA receptor blocker MK-801 (1.35 and 2.7 mg/kg), completely prevented the induction of seizure and bradyarrhythmia or sudden death resulting from seizure. Therefore, the white-noise-induced seizures in Mg-deficient rats are linked to increased neuronal excitability via the NMDA receptor.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Anticonvulsants; Body Weight; Dizocilpine Maleate; Electrocardiography; Electroencephalography; Electrolytes; Magnesium Deficiency; Male; Noise; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

The effects of the non-competitive N-methyl-D-aspartate (NMDA) antagonists, (+)-MK-801 hydrogen maleate (MK-801) and phencyclidine hydrochloride (PCP), were tested against hypoxia-induced tonic convulsions and hippocampal epileptiform discharges. Systemic administration of MK-801 and PCP suppressed the hypoxia-induced tonic convulsions in dietary Mg(2+)-deficient mice in a dose-dependent manner. The ED50 values (and their 95% confidence limits) of MK-801 and PCP were 0.19 (0.14-0.26) and 1.14 (0.32-4.11) mumol/kg, respectively. These values were lower than those of the conventional anticonvulsants tested. Induction of epileptiform discharges following hypoxia was also prevented by the presence of MK-801 and PCP at concentrations of 5-30 microM. The hypoxia-induced epileptiform discharges, however, were reduced, but not blocked completely, by the application of MK-801 and PCP. These results strongly suggest that activation of NMDA receptors in the hippocampus plays a pivotal role in the induction of hypoxia-induced tonic convulsions in dietary Mg(2+)-deficient mice.

Topics: Animals; Anticonvulsants; Dizocilpine Maleate; Hippocampus; Hypoxia; Magnesium Deficiency; Male; Membrane Potentials; Mice; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Seizures