dizocilpine-maleate and Coma

Rapid administration of large doses of ammonia leads to death of animals, which is largely prevented by pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists. The present study focuses on a subunit(s) of NMDA receptor involved in ammonia-induced death by use of NMDA receptor GluRepsilon subunit-deficient (GluRepsilon(-/-)) mice and the selective GluRepsilon2 antagonist CP-101,606. Acute ammonia intoxication was induced in mice (eight per group) by a single intraperitoneal (i.p.) injection of ammonium chloride. Appearance of neurological deteriorations depended on the doses of ammonium chloride injected. While wild-type, GluRepsilon1(-/-), GluRepsilon4(-/-), and GluRepsilon1(-/-)/epsilon4(-/-) mice all died by ammonium chloride at 12 mmol/kg during the first tonic convulsions, two of eight GluRepsilon3(-/-) mice survived. Pretreatment of wild-type mice with CP-101,606 prevented two mice from ammonia-induced death. Pretreatment of GluRepsilon3(-/-) mice with CP-101,606 prevented the death of three mice and prolonged the time of death of non-survivors. Similarly, the neuronal form of nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI) as well as the nonselective NOS inhibitor L-NMMA, but not the inducible NOS inhibitor 1400W, partially prevented the death of mice and prolonged the period of death. Furthermore, ammonium chloride prolonged the increase in intracellular free Ca2+ concentration ([Ca2+]i) and subsequent NO production induced by NMDA in the cerebellum. These results suggest that activation of NMDA receptor containing GluRepsilon2 and GluRepsilon3 subunits and following activation of neuronal NOS are involved in acute ammonia intoxication which leads to death of animals.

Topics: Ammonia; Animals; Calcium; Cerebellum; Coma; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures

Hypoglycemic coma increases extracellular excitatory amino acids, which mediate hypoglycemic neuronal degeneration. Cerebral oxygen consumption increases during hypoglycemic coma in piglets. We tested the hypothesis that the NMDA-receptor antagonist dizocilpine (MK801) attenuates the increase in cerebral oxygen consumption during hypoglycemia. We measured EEG, cerebral blood flow (CBF), cerebral oxygen consumption (CMRO(2)) and cortical microdialysate levels of glutamate, aspartate and glycine in pentobarbital-anesthetized piglets during 60 min of insulin-induced hypoglycemic coma. NMDA-receptor distribution was measured by autoradiography. MK801 (0.75 mg/kg i.v.) was given within 5 min after onset of isoelectric EEG. Saline- and MK801-treated normoglycemic control animals were also studied. Brain temperature was maintained at 38.5+/-0.5 degrees C. MK801 prevented the 5--10-fold increase in glutamate and aspartate occurring in saline-treated hypoglycemic animals, and attenuated the increase in CMRO(2). Increases in CBF of 200--400% during hypoglycemic coma were not affected by MK801. MK801 did not alter CBF, CMRO(2) or microdialysate amino acid levels in normoglycemic control animals. Parietal cortex corresponding to microdialysis sites was highly enriched in NMDA receptors, and the density and distribution overall of NMDA receptor binding sites were comparable to that reported in other species. We conclude that NMDA receptor activation plays a central role in hypoglycemia-induced glutamate release, and contributes to increased cerebral oxygen consumption. Neuroprotective effects of MK801 during hypoglycemia in piglets may involve inhibitory effects on glutamate release and oxidative metabolism.

Topics: Animals; Aspartic Acid; Brain Chemistry; Cerebrovascular Circulation; Coma; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Hypoglycemia; Microdialysis; Neurotoxins; Oxygen; Oxygen Consumption; Receptors, N-Methyl-D-Aspartate; Swine

Pretreatment of mice with 5-fluoromethylornithine (5FMOrn), a selective inactivator of ornithine aminotransferase, diminishes the accumulation of ammonia in the brain after administration of ammonium acetate, and antagonizes ammonia-induced fatal tonic extensor convulsions. In about 50% of the treated animals the loss of the righting reflex and coma is prevented. Presumably these effects are based on the enhancement of urea formation by the increased liver ornithine concentrations. However, since brain ornithine concentrations are greatly enhanced by 5FMOrn, it is not excluded that ornithine has direct effects on cellular events involved in ammonia-induced seizure generation, even though 5FMOrn had no anticonvulsant properties in a series of established animal seizure models, including N-methyl-D,L-aspartate-induced convulsions. NMDA receptor antagonists are capable of preventing death, but do not protect against the generation of coma and tonic extensor convulsions in ammonium acetate intoxicated mice. Since no evidence was found for ammonia-induced glutamate release from rat hippocampus, there is no convincing evidence for the idea that the tonic convulsions are mediated by NMDA receptors. L-Methionine-D, L-sulfoximine (MSO)-induced seizures can be partially antagonized by pretreatment with 5FMOrn. However, the effect is considerably smaller than against ammonia-induced convulsions, although at the time of seizure onset brain ammonia levels of MSO-intoxicated mice were lower than in the animals receiving ammonium acetate. This suggests that MSO-convulsions are not entirely due to the elevation of brain ammonia concentrations, even though MSO administration mimics effects of ammonia on cortical inhibitory neuronal interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3-Mercaptopropionic Acid; Ammonia; Animals; Brain Chemistry; Coma; Dialysis; Dizocilpine Maleate; Electroshock; Epilepsy, Generalized; Female; Glutamate-Ammonia Ligase; Methionine Sulfoximine; Mice; N-Methylaspartate; Ornithine; Ornithine-Oxo-Acid Transaminase; Pentylenetetrazole; Postural Balance; Putrescine; Strychnine

[3H]Glycine binding and glycine modulation of [3H]MK-801 binding have been used to study the glycine allosteric site associated with the N-methyl-D-aspartate receptor complex in postmortem human brain. The effect of glycine on [3H]MK-801 binding appeared sensitive to duration of terminal coma, and possibly postmortem delay. Thirty percent of the binding occurred in a subfraction of brain tissue and did not show enhancement by glycine and glutamic acid. [3H]Glycine binding to a subfraction free from this component was studied and showed high specific binding. KD and Bmax values showed considerable intersubject variability which did not appear to be due to demographic features or to tissue content of amino acids with an affinity for this site. The pharmacological characteristics of binding in this subfraction and a correlation between Bmax values and the maximal enhancement of [3H]MK-801 binding by glycine are consistent with [3H]glycine binding occurring to an N-methyl-D-aspartate receptor complex associated site. Further support for this is provided by a significantly lower Bmax value for [3H]glycine binding in subjects with Alzheimer's disease and reduced glycine enhancement of [3H]MK-801 binding. However, the effect of perimortem factors makes it difficult to confidently attribute this solely to a disease-related change in the receptor. The possible role of the glycine allosteric site in the treatment of neuropsychiatric disorders is discussed.

Topics: Aged; Aged, 80 and over; Allosteric Site; Alzheimer Disease; Animals; Cell Membrane; Cerebral Cortex; Coma; Dizocilpine Maleate; Female; Frontal Lobe; Glutamates; Glutamic Acid; Glycine; Humans; Male; Papio; Postmortem Changes; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate