dextrorphan and Seizures

Interest in developing NMDA receptor antagonists with reduced side-effects for neurological and psychiatric disorders has been re-energized by the recent introduction of esketamine into clinical practice for treatment-resistant depression. Structural analogs of dextromethorphan bind with low affinity to the NMDA receptor ion channel, have functional effects in vivo, and generally display a lower propensity for side-effects than that of ketamine and other higher affinity antagonists. As such, the aim of the present study was to determine whether a series of N-substituted-3-alkoxy-substituted dextromethorphan analogs produce their anticonvulsant effects through NMDA receptor blockade. Compounds were studied against NMDA-induced seizures in rats. Compounds were administered intracerebroventricularly in order to mitigate confounds of drug metabolism that arise from systemic administration. Comparison of the anticonvulsant potencies to their affinities for NMDA, σ1, and σ2 binding sites were made in order to evaluate the contribution of these receptors to anticonvulsant efficacy. The potencies to block convulsions were positively associated with their affinities to bind to the NMDA receptor ion channel ([

Topics: Alcohols; Animals; Anticonvulsants; Binding Sites; Dextromethorphan; Dextrorphan; Disease Models, Animal; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Infusions, Intraventricular; Ligands; Male; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Seizures; Sigma-1 Receptor; Treatment Outcome

Dextrorphan, a major metabolite of dextromethorphan, produces the duration of spinal and cutaneous anesthesia similar to bupivacaine. The purpose of this study was to test the central nervous system and cardiovascular toxicity of bupivacaine, dextromethorphan, and dextrorphan.. First, dose-response curves for dextromethorphan, dextrorphan, and bupivacaine (n = 8 at each testing point) were determined for cutaneous analgesia on the rat back, and equipotent doses were calculated. Next, during continuous intravenous infusion of equipotent doses of bupivacaine, dextromethorphan, and dextrorphan (n = 8 in each group), we observed the time to seizure, apnea, and complete cardiac arrest. A saline group (n = 7) was used for comparison. Mean arterial blood pressure (MAP), heart rate (HR), stroke volume (SV), and cardiac output (CO) were also monitored.. Bupivacaine, dextromethorphan, and dextrorphan produced dose-dependent cutaneous anesthesia. A longer duration of equipotent infusion doses was required to produce seizures in the dextromethorphan group (10.6 ± 1.3 min) than in the bupivacaine group (7.6 ± 2.1 min) (P = 0.005). Dextrorphan did not produce any seizures. Compared with bupivacaine, time to apnea and complete cardiac arrest was longer with dextrorphan (P < 0.001) and with dextromethorphan (P = 0.001). Cardiovascular collapse, defined as a decline in MAP, HR, CO, and SV, was slower in the dextromethorphan and dextrorphan groups than in the bupivacaine group (P < 0.001 for both comparisons).. At equipotent doses for local anesthesia, dextromethorphan and dextrorphan were less likely than bupivacaine to induce central nervous system and cardiovascular toxicity.

Topics: Anesthetics, Local; Animals; Apnea; Bupivacaine; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Heart Arrest; Infusions, Intravenous; Male; Rats; Rats, Sprague-Dawley; Seizures; Time Factors

The effects of dextromethorphan (DM), and its major metabolite dextrorphan (DX) on kainic acid-induced seizures in mice were examined. Intracerebroventricular DM or DX (5 or 10 microg/0.5 microl) pretreatment significantly attenuated seizures induced by kainic acid (0.07 microg/0.07 microl) in a dose-related manner. DM or DX pretreatment significantly attenuated kainic acid-induced increases in AP-1 DNA-binding activity and fos-related antigen-immunoreactivity as well as neuronal loss in the hippocampus. DM appears to be a more potent neuroprotectant than DX. Since the high-affinity DM binding sites are recognized as being identical to the sigma-1 site, we examined the role of the sigma-1 receptor on the pharmacological action mediated by DM or DX. Pretreatment with the sigma-1 receptor antagonist BD1047 (2.5 or 5 mg/kg, i.p.) blocked the neuroprotection by DM in a dose-related manner. This effect of BD 1047 was more pronounced in the animals treated with DM than in those treated with DX. Combined, our results suggest that metabolism of DM to DX is not essential for DM to exert its effect. They also suggest that DM provides neuroprotection from kainic acid via sigma-1 receptor modulation.

Topics: Animals; Anticonvulsants; Dextromethorphan; Dextrorphan; DNA; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hippocampus; Injections, Intraventricular; Kainic Acid; Male; Mice; Mice, Inbred DBA; Neurons; Proto-Oncogene Proteins c-fos; Receptors, Opioid, delta; Seizures; Transcription Factor AP-1

BAY k-8644 (an L-type Ca(2+) channel agonist of the dihydropyridine class) is recognized as a potent convulsant agent. In this study, we used BAY k-8644 to explore the effects of dextromethorphan (DM) and its major metabolite, dextrorphan (DX), on the (pro)convulsant activity regulated by calcium channels. BAY k-8644 (2 mg/kg, s.c) potentiated seizures induced in rats by kainic acid (KA) (10 mg/kg, i.p.). DM appears more efficacious than DX in attenuation of KA-induced seizures. The anticonvulsant effect of a low dose (12.5 mg/kg, s.c.) of DM was reversed by BAY k-8644 (2 mg/kg) challenge. In contrast, BAY k-8644 (1 or 2 mg/kg) did not significantly affect an anticonvulsant effect from a higher dose (25 mg/kg) of either DM or DX. Intracerebroventricular injection of BAY k-8644 (37.5 microg) significantly induced seizures in mice. DM (12.5 or 25 mg/kg) pretreatment more significantly attenuated seizures evoked by BAY k-8644 than did DX (12.5 or 25 mg/kg). Furthermore, seizure activity induced by KA or BAY k-8644 was consistent with respective activator protein-1 DNA binding activity of the hippocampus. Therefore, our results suggest that the anticonvulsant effects of the morphinans involve, at least in part, the L-type calcium channel. They also suggest that DM is a more potent anticonvulsant than DX in the KA and BAY k-8644 seizure models.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Anticonvulsants; Calcium Channel Agonists; Dextromethorphan; Dextrorphan; Excitatory Amino Acid Agonists; Kainic Acid; Male; Mice; Mice, Inbred DBA; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Seizures; Transcription Factor AP-1

Methcathinone, a designer drug, has high abuse liability. In this study we characterized acute methcathinone toxicity in rats, attempting to determine whether the excitatory amino acid receptor antagonist dextrorphan can antagonize methcathinone intoxication.. Intoxication was produced with IV methcathinone infusion (5 mg/kg/minute; 100 mg/mL) in conscious rats. We studied pretreatment, in which dextrorphan or vehicle was injected 30 minutes before methcathinone infusion. In a second protocol, dextrorphan or saline solution was given immediately after the onset of convulsions.. Methcathinone caused tachycardia (maximal increase, 131 +/- 10 beats/minute), hyperthermia (+2.3 degrees C), convulsions, and cardiorespiratory collapse in vehicle-pretreated rats (n = 9). Death occurred after 32.0 +/- 1.1 minutes of infusion. Dextrorphan pretreatment (25 mg/kg; n = 7) significantly reduced hyperthermia (+.1 degree +/- .3 degree C) and tachycardia and increased the convulsive (dextrorphan, 134 +/- 9 mg/kg; vehicle, 67 +/- 4 mg/kg) and lethal doses (dextrorphan, 204 +/- 9 mg/kg; vehicle, 160 +/- 5 mg/kg). Dextrorphan, given immediately after the initial methcathinone convulsion, reduced hyperthermic and tachycardic responses but not the lethality of methcathinone.. Blockade of excitatory amino acid receptors by dextrorphan minimizes acute methcathinone intoxication.

Topics: Animals; Designer Drugs; Dextrorphan; Fever; Lethal Dose 50; Male; Propiophenones; Rats; Rats, Sprague-Dawley; Receptors, Amino Acid; Seizures; Tachycardia; Time Factors

Nonketotic hyperglycinaemia (NKH) is an inborn error of the glycine cleavage system resulting in seizures and mental retardation. Two prior reports noted an anticonvulsant effect from high-dose dextromethorphan (DM) in this disorder, although the two reported patients demonstrated widely disparate DM requirements and drug levels. We report two children with NKH who also demonstrated disparate and variable DM metabolism which markedly influenced the dose-concentration-response relationship. Levels of DM and its primary metabolite dextrorphan (DX) were utilized to guide DM therapy and exhibited patterns reflective of the extensive and poor metabolizer phenotypes for CYP2D6, the cytochrome P450 isoform responsible for DM metabolism. In the patient who appeared to represent the extensive metabolizer (EM) phenotype, treatment with the non-specific cytochrome P450 inhibitor cimetidine was required to reduce biotransformation of DM to DX and, thus, to increase DM plasma concentrations. In the patient with the apparent poor metabolizer (PM) phenotype, a change in the DM preparation to a sustained-release form and increase in the dosing interval was required to lower DM plasma concentrations. These cases demonstrate the importance of CYP2D6 phenotype in providing safe and effective DM therapy to patients with NKH.

Topics: Child; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Female; Humans; Hyperglycemic Hyperosmolar Nonketotic Coma; Infant, Newborn; N-Methylaspartate; Seizures

Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and antiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N-methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.

Topics: Animals; Calcium Channels; Cells, Cultured; Dextromethorphan; Dextrorphan; Electrophysiology; Evoked Potentials; Humans; Ion Channels; Neurons; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Sodium Channels

The present experiments examined whether pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801 and dextrorphan, could antagonize cocaine-induced convulsions and lethality in conscious Sprague-Dawley (SD) rats and whether urethane anesthesia alters the observed interactions. Conscious, restrained male SD rats received continuous i.v. infusions of cocaine hydrochloride (1.25 mg/kg.min) until convulsions and death occurred. Cocaine doses of 21.2 +/- 1.8 and 29.5 +/- 2.5 mg/kg caused convulsions and death, respectively, in saline treated rats (n = 8). Convulsions were absent in MK-801 (1 mg/kg, i.v.; n = 8) pretreated rats; the lethal cocaine dose was 44.0 +/- 2.7 mg/kg (p < 0.05). In contrast, urethane anesthesia (1.2 g/kg, i.p.) decreased the dose of cocaine required to cause toxicity, compared to that in saline controls (24.8 +/- 0.8 mg/kg, n = 13), in MK-801 (2.0 +/- 0.3, n = 7; p < 0.01) and in dextrorphan mg/kg, n = 13), in MK-801 (2.0 +/- 0.3, n = 7; p < 0.01) and in dextrorphan (25 mg/kg, i.v.; 13.1 +/- 1.4, n = 6; p < 0.01) pretreated rats. Pressor responses with little change in heart rate were evident during cocaine infusion in vehicle pretreated rats. Bradycardiac responses were noted to cocaine in groups following NMDA receptor blockade. Reversal of the pressor response to cocaine was noted in MK-801 pretreated animals, while dextrorphan pretreatment moderated cocaine-induced increases in blood pressure. Ventilatory support protected against cocaine lethality in urethane anesthetized rats, indicating that respiratory failure is the proximate cause of death with cocaine infusion. However, artificially ventilated rats, pretreated with MK-801, were more sensitive (lethal cocaine dose, 76.6 +/- 8.0 mg/kg, n = 5) than vehicle pretreated rats (129.4 +/- 15.8 mg/kg, n = 6), indicating that MK-801 may increase both the respiratory and the cardiac toxicity of cocaine in urethane anesthetized rats. Interactions between NMDA receptors and cocaine are modified by urethane anesthesia.

Topics: Anesthesia; Animals; Blood Pressure; Body Temperature; Cocaine; Consciousness; Dextrorphan; Dizocilpine Maleate; Drug Interactions; Heart Rate; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Respiration Disorders; Seizures; Urethane

The anticonvulsant and adverse effects of dextromethorphan, a non-opioid antitussive, and its metabolite dextrorphan were examined in amygdala-kindled rats. Both drugs have repeatedly been proposed to be functional non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, but they also exert effects distinct from antagonism at NMDA receptors, such as blockade of voltage-gated calcium channels and sigma-site mediated actions. Since recent data have demonstrated that kindled rats are more susceptible to the adverse effects of NMDA receptor antagonists than non-kindled rats, the time course, characteristics and severity of adverse effects of dextromethorphan and dextrorphan were also determined in non-kindled animals. Dextromethorphan dose dependently increased the focal seizure threshold (i.e. the threshold for induction of afterdischarges recorded from the amygdala) in fully kindled rats. This anticonvulsant effect was found at relatively low doses (7.5-15 mg/kg i.p.) which were almost free of any adverse effects. At higher doses, dextromethorphan induced motor impairment and seizures, but no phenyclidine (PCP)-like adverse effects, such as hyperlocomotion or stereotypies. In contrast, such adverse effects were seen after dextrorphan, although only infrequently. Dextrorphan was less potent in inducing anticonvulsant but more potent in inducing motor impairing effects than dextromethorphan in kindled rats. In non-kindled rats, the motor impairment induced by dextrorphan was significantly less severe than in kindled rats, whereas no marked differences between kindled and non-kindled rats were found for dextromethorphan. The data indicate that dextromethorphan and dextrorphan differ in their mechanisms of action. Only dextrorphan exerts effects which are characteristic for NMDA receptor antagonism, whereas the potent anticonvulsant effect of dextromethorphan in presumably unrelated to the NMDA receptor complex.

Topics: Amygdala; Animals; Anticonvulsants; Dextromethorphan; Dextrorphan; Female; Kindling, Neurologic; Motor Activity; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Topics: Dextromethorphan; Dextrorphan; Glycine; Humans; Infant; Ketosis; Receptors, N-Methyl-D-Aspartate; Seizures

Topics: Animals; Anticonvulsants; Cocaine; Death; Dextrorphan; Dizocilpine Maleate; Glutamates; Kynurenic Acid; Male; Mice; Mice, Inbred ICR; Neurotoxins; Piperazines; Receptors, Neurotransmitter; Seizures

The involvement of excitatory amino acid (EAA) receptors in mediation of the toxic effects of cocaine was studied in male ICR mice. Cocaine HCl (90 mg/kg, IP) induced seizures in 95% and death within 24 h in 68% (n = 135) of the animals. There was a significant correlation (r = .54) between the time to onset of convulsions and the time to death in mice which died within 30 min of injection (n = 84). Pretreatment with selected EAA receptor antagonists 15 min prior to cocaine differentially blocked cocaine toxicity. Selective N-methyl-D-aspartic acid (NMDA) receptor antagonists (MK-801, dextrorphan, CPP) decreased both the incidence of seizures and mortality. A nonselective EAA antagonist, kynurenic acid, decreased lethality in doses which did not reduce convulsions. A similar action was observed following pretreatment with the selective kainic acid/AMPA receptor antagonist, GDEE. Antagonists at EAA receptors can provide significant protection against cocaine-induced toxicity. Moreover, the data provide evidence for the involvement of both NMDA and non-NMDA receptor subtypes in aspects of cocaine toxicity.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Anticonvulsants; Cocaine; Death; Dextrorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutamates; Kynurenic Acid; Male; Mice; Mice, Inbred ICR; Piperazines; Quinoxalines; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Time Factors

The antitussive, dextromethorphan (DM), and its metabolite, dextrorphan (DX), were evaluated for antiepileptic properties in vitro. Interictal bursts and prolonged ictal epileptiform afterdischarges, induced by perfusion of guinea pig neocortical brain slices with Mg2+-free solution, were blocked by DX (1-250 microM) or DM (100 microM). Intracellular records showed that these agents blocked N-methyl-D-aspartate (NMDA)-induced depolarizations without altering intrinsic membrane properties. DX blocked NMDA but not quisqualate-evoked multi-unit excitatory responses. DM is a widely available, orally effective drug with low toxicity in antitussive doses, which has antiepileptic and NMDA-antagonist properties in vitro. Its toxicity and effectiveness as an anticonvulsant should be expeditiously examined in clinical trials.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Antitussive Agents; Aspartic Acid; Cerebral Cortex; Dextromethorphan; Dextrorphan; Evoked Potentials; Guinea Pigs; In Vitro Techniques; Levorphanol; Morphinans; N-Methylaspartate; Seizures; Valine

Opiate alkaloid and opioid peptide actions on spontaneous neuronal activity and postsynaptic amino acid responsiveness were assessed using intracellular recording techniques applied to murine spinal cord neurons in primary dissociated cell culture. Application of opiates was by superfusion and amino acids by iontophoresis. Glycine and GABA but not glutamate responses were antagonized by the opiate alkaloids. Since opiate effects on glycine and GABA responses were not naloxone-reversible, only weakly stereospecific, and not produced by the opioid peptide [D-Ala2]-Met-enkephalinamide, it is unlikely that these effects were mediated by opiate receptors. Opiate depression of glycine inhibition was correlated with the induction of paroxysmal depolarizations in cultured spinal cord neurons, suggesting that antagonism of inhibitory amino acid transmission may underlie the convulsant actions of high concentrations of the opiate alkaloids.

Topics: Animals; Cells, Cultured; Dextrorphan; Enkephalin, Methionine; Enkephalins; Evoked Potentials; gamma-Aminobutyric Acid; Glycine; Levorphanol; Mice; Morphine; Naloxone; Narcotics; Neural Inhibition; Neurons; Seizures; Spinal Cord; Synapses