dizocilpine-maleate and Carbon-Monoxide-Poisoning

We measured changes in nitric oxide (NO) concentration in the cerebral cortex during experimental carbon monoxide (CO) poisoning and assessed the role for N-methyl-d-aspartate receptors (NMDARs), a glutamate receptor subtype, with progression of CO-mediated oxidative stress. Using microelectrodes, NO concentration was found to nearly double to 280 nM due to CO exposure, and elevations in cerebral blood flow, monitored as laser Doppler flow (LDF), were found to loosely correlate with NO concentration. Neuronal nitric oxide synthase (nNOS) activity was the cause of the NO elevation based on the effects of specific NOS inhibitors and observations in nNOS knockout mice. Activation of nNOS was inhibited by the NMDARs inhibitor, MK 801, and by the calcium channel blocker, nimodipine, thus demonstrating a link to excitatory amino acids. Cortical cyclic GMP concentration was increased due to CO poisoning and shown to be related to NO, versus CO, mediated guanylate cyclase activation. Elevations of NO were inhibited when rats were infused with superoxide dismutase and in rats depleted of platelets or neutrophils. When injected with MK 801 or 7-nitroindazole, a selective nNOS inhibitor, rats did not exhibit CO-mediated nitrotyrosine formation, myeloperoxidase (MPO) elevation (indicative of neutrophil sequestration), or impaired learning. Similarly, whereas CO-poisoned wild-type mice exhibited elevations in nitrotyrosine and myeloperoxidase, these changes did not occur in nNOS knockout mice. We conclude that CO exposure initiates perivascular processes including oxidative stress that triggers activation of NMDA neuronal nNOS, and these events are necessary for the progression of CO-mediated neuropathology.

Topics: Animals; Brain Chemistry; Calcium Channel Blockers; Carbon Monoxide Poisoning; Cyclic GMP; Dizocilpine Maleate; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Indazoles; Laser-Doppler Flowmetry; Male; Maze Learning; Mice; Mice, Knockout; Microelectrodes; Neurons; Neurotoxicity Syndromes; Neutropenia; Neutrophils; NG-Nitroarginine Methyl Ester; Nimodipine; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Platelet Count; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Tyrosine

Carbon monoxide (CO) poisoning caused by CO exposure at 3000 ppm for 40 min resulted in stimulation of hydroxyl radical (*OH) generation (estimated by measuring 2,3-dihydroxybenzoic acid (2,3-DHBA) production from salicylic acid) in the striatum of free-moving rats, as determined by means of brain microdialysis. Pretreatment with a voltage-dependent Na+ channel blocker, tetrodotoxin (TTX), lowered the basal level of 2,3-DHBA and strongly suppressed the increase in 2,3-DHBA induced by CO poisoning. CO poisoning significantly, though only slightly, increased extracellular glutamate in the striatum, and glutamate (Glu) receptor antagonists, such as MK-801 (dizocilpine) and NBQX, failed to suppress the CO-induced increase in 2,3-DHBA. These findings suggest that CO poisoning may induce Na+ influx via the voltage-dependent Na+ channels, resulting in stimulation of *OH generation in rat striatum. This effect may be independent of Glu receptor activation by increased extracellular Glu.

Topics: Animals; Carbon Monoxide Poisoning; Corpus Striatum; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Hydroxybenzoates; Hydroxyl Radical; Male; Microdialysis; Quinoxalines; Rats; Rats, Sprague-Dawley; Tetrodotoxin; Wakefulness

The neuroactive steroids pregnenolone (3beta-hydroxy-5-pregnen-20-one) and dehydroepiandrosterone (DHEA, 3alpha-hydroxy-5-androstene-17-one) are negative allosteric modulators of the GABA(A) receptors and positive modulators of acetylcholine, NMDA and sigma(1) receptors. Pregnenolone was recently shown to potentiate the neuronal damage induced by excessive glutamate in cell culture models, whereas dehydroepiandrosterone was reported to present some neuroprotective activity. The in vivo relevance of these effects was investigated in mice submitted to an hypoxic insult, the repeated exposure to carbon monoxide (CO) gas, a model that leads to neurodegeneration in the CA(1) hippocampal area and learning deficits. Recording spontaneous alternation behaviour in the Y-maze assessed short-term memory and long-term memory was examined using a passive avoidance task. After exposure to CO, mice showed a progressive deterioration of their learning ability, reaching significance after 3 days and being maximal after 7 days. Pregnenolone administered before CO significantly facilitated the hypoxia-related deficits, which could be measured 1 day after CO and appeared maximal after 3 days. Dizocilpine blocked the deficits in vehicle- and pregnenolone-treated CO-exposed animals, showing that pregnenolone selectively facilitated the NMDA receptor-dependent excitotoxicity. Dehydroepiandrosterone blocked the appearance of the CO-induced deficits, even after 7 days. Interestingly, the sigma(1) receptor antagonist N, N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) failed to affect the dehydroepiandrosterone-induced protection, showing the lack of involvement of sigma(1) receptors. Cresyl violet-stained sections of the mouse hippocampal formation showed that the neurodegeneration observed in the CA(1) area after exposure to CO was augmented by pregnenolone and blocked by dehydroepiandrosterone. These results show that pregnenolone and dehydroepiandrosterone, although being similarly involved in modulating the excitatory/inhibitory balance in the brain, do not equally affect the extent of excitotoxic insults.

Topics: Animals; Anisoles; Antipsychotic Agents; Behavior, Animal; Carbon Monoxide Poisoning; Dehydroepiandrosterone; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Learning; Male; Memory; Memory, Short-Term; Mice; Nerve Degeneration; Pregnenolone; Propylamines

The effects of dynorphin A (1-13) on carbon monoxide (CO)-induced amnesia in mice were investigated. Memory deficiency was apparent during Y-maze testing 5 days after CO exposure (delayed amnesia). Percent alternation in the CO-exposed group was significantly lower than that in the control group. Administration of dynorphin A (1-13) (1.5 nmol, i.c.v.) 15 min before the Y-maze test session reversed the impairment of spontaneous alternation performance in the CO-exposed group. To determine whether this effect was mediated via kappa opioid receptors, we attempted to block the effect of dynorphin A using the kappa opioid receptor antagonist nor-binaltorphimine. Nor-binaltorphimine (5.44 nmol, i.c.v.) blocked the effect of dynorphin A (1-13) on delayed amnesia. Dynorphin A (1-13) did not affect the impairment of alternation induced by the blockade of NMDA-receptors by dizocilpine (MK-801), but significantly prevented the impairment induced by mecamylamine. These results suggest that dynorphin A (1-13) modulates the kappa receptor-mediated opioid neuronal system, and reverses the impairment of spontaneous alternation performance induced by CO exposure.

Topics: Amnesia; Animals; Carbon Monoxide Poisoning; Dizocilpine Maleate; Dynorphins; Excitatory Amino Acid Antagonists; Injections, Intraventricular; Male; Maze Learning; Mecamylamine; Mice; Mice, Inbred Strains; Naltrexone; Narcotic Antagonists; Narcotics; Nicotinic Antagonists; Peptide Fragments; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, kappa

The mechanism of neurodegeneration and the possible therapeutic amelioration were investigated in a model induced by successive carbon monoxide (CO) exposures. Successive CO exposures resulted in a consistent pattern of degeneration of hippocampal CA1 pyramidal cells, which was quantified using an image analyzer. Competitive and noncompetitive antagonists of N-methyl-D-aspartate (NMDA) receptors, cyclopentenophenanthrene, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten,5,10-imine maleate and an antagonist of glycine binding sites, 7-chlorokynurenic acid, significantly reduced the CO-induced neurodegeneration. Ifenprodil (a antagonist of polyamine binding sites) and glycine had no effect. From these results, it is clear that NMDA receptor/ion channel complex is involved in the mechanism of CO-induced neurodegeneration, and that glycine binding site antagonist as well as NMDA competitive and noncompetitive antagonists may have neuroprotective properties in neurological disorders associated with overactivation of NMDA receptors.

Topics: Animals; Binding Sites; Carbon Monoxide Poisoning; Dizocilpine Maleate; Glycine; Hippocampus; Male; Mice; Piperidines; Receptors, N-Methyl-D-Aspartate; Vasodilator Agents