dextromethorphan and Disease-Models--Animal

dextromethorphan has been researched along with Disease-Models--Animal* in 39 studies

Reviews

2 review(s) available for dextromethorphan and Disease-Models--Animal

ArticleYear
Where are the new cough treatments: a debriefing of recent clinical proof-of-concept trials with the NOP agonist SCH 486757.
    Pharmacology, 2011, Volume: 88, Issue:1-2

    Cough continues to be one of the top reasons why patients seek medical attention from health care providers. The prescription antitussive market is dominated by opioids, such as codeine that produces inconsistent efficacy and is often accompanied by significant side effect liabilities. Consequently, cough represents an unmet medical need and an underserved market. Yet, against the backdrop of increasing cough research, the development of novel treatments has been exceptionally challenging with dextromethorphan being the last US drug approved for cough almost a half century ago. We support the position that an unambiguous and actionable 'road map' that clearly delineates the pathway forward for new cough suppressants from basic research to and beyond clinical proof-of-concept studies will be an important aspect for future success of this pharmacological class of drug. Pivotal to the establishment of such a road map will be the review of lessons learned from antitussive agents that have been recently progressed to proof-of-concept trials. In the present commentary, we briefly discuss observations and challenges pertaining to SCH 486757, a selective orally active NOP agonist that has recently advanced to human antitussive testing.

    Topics: Animals; Antitussive Agents; Azabicyclo Compounds; Clinical Trials as Topic; Codeine; Cough; Dextromethorphan; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Guinea Pigs; Humans; Nociceptin; Opioid Peptides; Pyrimidines; Rats; Receptors, Opioid

2011
[NMDA receptor antagonists: a new treatment for neuropathic pain].
    Harefuah, 1999, Apr-02, Volume: 136, Issue:7

    Topics: Animals; Clinical Trials as Topic; Dextromethorphan; Disease Models, Animal; Excitatory Amino Acid Antagonists; Humans; Memantine; Neuralgia; Receptors, N-Methyl-D-Aspartate

1999

Other Studies

37 other study(ies) available for dextromethorphan and Disease-Models--Animal

ArticleYear
Discovery and development of novel pyrimidine and pyrazolo/thieno-fused pyrimidine derivatives as potent and orally active inducible nitric oxide synthase dimerization inhibitor with efficacy for arthritis.
    European journal of medicinal chemistry, 2021, Mar-05, Volume: 213

    In order to discover and develop drug-like anti-inflammatory agents against arthritis, based on "Hit" we found earlier and to overcome drawbacks of toxicity, twelve series of total 89 novel pyrimidine, pyrazolo[4,3-d]pyrimidine and thieno[3,2-d]pyrimidine derivatives were designed, synthesized and screened for their anti-inflammatory activity against NO and toxicity for normal liver cells (LO2). Relationships of balance toxicity and activity have been summarized through multi-steps, and title compounds 22o, 22l were found to show lower toxicity (against LO2: IC

    Topics: Administration, Oral; Animals; Arthritis; Cells, Cultured; Dimerization; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Development; Enzyme Inhibitors; Freund's Adjuvant; Humans; Lipopolysaccharides; Male; Mice; Molecular Structure; Nitric Oxide; Nitric Oxide Synthase Type II; Pyrazoles; Pyrimidines; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Structure-Activity Relationship

2021
Ouabain inhibitor rostafuroxin attenuates dextromethorphan-induced manic potential.
    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2021, Volume: 158

    Dextromethorphan (DM) abuse produces mania-like symptoms in humans. ERK/Akt signaling activation involved in manic potential can be attenuated by the inhibition of ouabain-like cardiac steroids. In this study, increased phosphorylations of ERK/Akt and hyperlocomotion induced by DM (30 mg/kg, i.p./day × 7) were significantly protected by the ouabain inhibitor rostafuroxin (ROSTA), suggesting that DM induces the manic potential. ROSTA significantly attenuated DM-induced protein kinase C δ (PKCδ) phosphorylation, GluN2B (i.e., MDA receptor subunit) expression, and phospho-PKCδ/GluN2B interaction. DM instantly upregulated the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent system. However, DM reduced Nrf2 nuclear translocation, Nrf2 DNA binding activity, γ-glutamylcysteine mRNA expression, and subsequent GSH/GSSG level and enhanced oxidative parameters following 1-h of administration. ROSTA, PKCδ inhibitor rottlerin, and GluN2B inhibitor traxoprodil significantly attenuated DM-induced alterations in Nrf2-related redox parameters and locomotor activity induced by DM in wild-type mice. Importantly, in PKCδ knockout mice, DM failed to alter the above parameters. Further, ROSTA and traxoprodil also failed to enhance PKCδ depletion effect, suggesting that PKCδ is a critical target for the anti-manic potential of ROSTA or GluN2B antagonism. Our results suggest that ROSTA inhibits DM-induced manic potential by attenuating ERK/Akt activation, GluN2B/PKCδ signalings, and Nrf2-dependent system.

    Topics: Androstanols; Animals; Bipolar Disorder; Dextromethorphan; Disease Models, Animal; Locomotion; Male; Mice; Ouabain; Signal Transduction

2021
N-Substituted-3-alkoxy-derivatives of dextromethorphan are functional NMDA receptor antagonists in vivo: Evidence from an NMDA-induced seizure model in rats.
    Pharmacology, biochemistry, and behavior, 2021, Volume: 203

    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

2021
Dextromethorphan and bupropion reduces high level remifentanil self-administration in rats.
    Pharmacology, biochemistry, and behavior, 2020, Volume: 193

    Opiate addiction has risen substantially during the past decade. New treatments to combat opiate addiction are sorely needed. The current study was conducted to determine the acute individual and interactive effects of bupropion and dextromethorphan in a rat model of opiate self-administration using the short-acting synthetic opioid remifentanil. Both of these drugs have been found to reduce self-administration of nicotine. Bupropion and dextromethorphan and their combination had differential effects depending on whether the rats showed higher or lower baseline remifentanil self-administration. The rats with higher initial remifentanil self-administration showed a significant decrease in remifentanil self-administration with bupropion or dextromethorphan treatment, compared to the vehicle control condition. This decrease in self-remifentanil administration was most pronounced when combination of the higher doses of bupropion and dextromethorphan were administered. In contrast, the rats with lower baseline remifentanil self-administration showed the opposite effect of drug treatment with an increase in remifentanil self-administration with bupropion treatment compared to the vehicle control condition. Dextromethorphan had no significant effect inthis group. This study shows that combination bupropion and dextromethorphan affects remifentanil self-administration in a complex fashion with differential effects on low and high baseline responders. In subjects with high baseline remifentanil self-administration, bupropion and dextromethorphan treatment significantly reduced self-administration, whereas in subjects with low baseline remifentanil self-administration, bupropion increased remifentanil self-administration and dextromethorphan had no discernible effect. This finding suggests that combination bupropion-dextromethorphan should be tested in humans, with a focus on treating people with high-level opiate use.

    Topics: Analgesics, Opioid; Animals; Behavior, Animal; Bupropion; Dextromethorphan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Locomotion; Motivation; Opioid-Related Disorders; Rats; Rats, Sprague-Dawley; Remifentanil; Self Administration; Treatment Outcome

2020
Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice.
    Brain : a journal of neurology, 2020, 07-01, Volume: 143, Issue:7

    NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard anti-epileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.

    Topics: Animals; Dextromethorphan; Disease Models, Animal; Epilepsy, Generalized; Excitatory Amino Acid Antagonists; Gene Knock-In Techniques; Humans; Infant; Male; Memantine; Mice; Neurodevelopmental Disorders; Receptors, N-Methyl-D-Aspartate

2020
The effect of dextromethorphan use in Parkinson's disease: A 6-hydroxydopamine rat model and population-based study.
    European journal of pharmacology, 2019, Nov-05, Volume: 862

    This study investigated the effect of dextromethorphan (DXM) against Parkinson's disease (PD) in rats and explored the association between DXM dose and PD risk in elderly patients 65 years and older using a population-based database. The PD rat model (Sprague Dawley rats) was induced by injecting 6-hydroxydopamine (6-OHDA) into the unilateral medial forebrain bundle of the rat brain. DXM (20 mg/kg) was administered intraperitoneally twice daily from 7 days before the appearance of a 6-OHDA lesion to 28 days after the lesion appeared. The availability of dopamine transporter (DAT) and serotonin transporter (SERT) in the striatum of the rat brain was measured using positron emission tomography. The apomorphine-induced rotation test was performed to study the hypersensitivity of the brain regions with lesions. This animal study demonstrated that DXM significantly attenuated 6-OHDA-induced DAT and SERT loss, correlating to rotational behaviors. The population-based human study analyzed the data from the Taiwan Longitudinal Health Insurance Database 2005 between January 2005 and December 2013 and then used the DXM dose-response curve to investigate the trend of its protective effect against PD. In the human study, low cumulative doses of DXM may potentially achieve a protective effect for PD; however, high cumulative doses seem to be a risk for PD.

    Topics: Aged; Aged, 80 and over; Animals; Behavior Observation Techniques; Behavior, Animal; Case-Control Studies; Corpus Striatum; Dextromethorphan; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Female; Humans; Male; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Positron-Emission Tomography; Protective Agents; Rats; Rats, Sprague-Dawley; Serotonin Plasma Membrane Transport Proteins; Taiwan; X-Ray Microtomography

2019
Desferrioxamine and dextromethorphan combination exhibited synergistic effect and reversed the catalepsy behaviour in 6-hydroxydopamine hydroydopamine administered rats through regulating brain glutamate levels.
    The Journal of pharmacy and pharmacology, 2019, Volume: 71, Issue:8

    To investigate the effect of desferrioxamine (DFO) and dextromethorphan (DXM) combination in animal model of Parkinson's disease (PD).. The PD was induced in rats through intracerebroventricular administration of 6-hydroxydopamine (6-OHDA) using stereotaxic apparatus. The animals were subjected to behavioural assessments and neurobiochemicals estimation followed by immunohistochemistry staining of neuron specific enolase (NSE) in striatum.. Desferrioxamine and DXM combination has significantly reversed the catalepsy behaviour and elevated the antioxidant enzymes (SOD, CAT, GSH) and dopamine levels. Interestingly, the level of glutamate, nitric oxide, cytokines (IL-1β, TNF-α) and NSE expressions were found to be decreased in striatum region of 6-OHDA-administered rats. The combination of DFO and DXM has shown synergism in most of the parameters studied, when compared to per se treatment.. The reversal of catalepsy behaviour represents the protective effect of above combination on dopamine neurons in striatum from 6-OHDA toxicity. The mechanism of DFO and DXM combination might be attributed through attenuation of glutamate-induced excitotoxicity in neurons through ameliorating the reactive oxygen species and pro-inflammatory cytokines release. Treatment with DFO and DXM combination could control the multiple events in the pathogenesis of PD.

    Topics: Animals; Antioxidants; Catalepsy; Corpus Striatum; Deferoxamine; Dextromethorphan; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Drug Combinations; Drug Synergism; Glutamic Acid; Hydroxydopamines; Male; Neuroprotective Agents; Parkinson Disease; Rats; Rats, Wistar

2019
Evaluation of brain SERT with 4-[
    Toxicology and applied pharmacology, 2019, 09-01, Volume: 378

    This study investigated the protective effects of dextromethorphan (DXM) on noise-induced hearing loss (NIHL) in rats. This study aimed to improve the auditory threshold and to understand the protective effects of DXM against N-methyl-d-aspartate (NMDA)-induced neurite degeneration of serotonergic neurons. The animals were exposed to 8-kHz narrowband noise at a 118-dB sound pressure level for 3.5 h. The hearing thresholds were determined by measuring the auditory brainstem response to click stimuli. Serotonin transporter (SERT) expression was determined through micro-positron emission tomography (PET) using N,N-dimethyl-2-(2-amino-4-

    Topics: Animals; Benzylamines; Brain; Brain Stem; Dextromethorphan; Disease Models, Animal; Evoked Potentials, Auditory, Brain Stem; Hearing Loss; Male; N-Methylaspartate; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; RNA-Binding Proteins; Serotonergic Neurons; Serotonin Plasma Membrane Transport Proteins

2019
Protective effect of Lycium Barbarum polysaccharides on dextromethorphan-induced mood impairment and neurogenesis suppression.
    Brain research bulletin, 2017, Volume: 134

    Dextromethorphan (DXM) is one of the common drugs abused by adolescents. It is the active ingredient found in cough medicine which is used for suppressing cough. High dosage of DXM can induce euphoria, dissociative effects and even hallucinations. Chronic use of DXM may also lead to depressive-related symptoms. Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of ageing-related neurodegenerative diseases. A recent study has shown the potential beneficial effect of Lycium barbarum to reduce depression-like behavior. In the present study, we investigated the role of Lycium barbarum polysaccharide (LBP) to alleviate DXM-induced emotional distress. Sprague Dawley rats were divided into 4 groups (n=6 per group), including the normal control (vehicles only), DXM-treated group (40 mg/kg DXM), LBP-treated group (1 mg/kg LBP) and DXM+ LBP-treated group (40 mg/kg DXM and 1 mg/kg LBP). After two-week treatment, the DXM-treated group showed increased depression-like and social anxiety-like behaviors in the forced swim test and social interaction test respectively. On the other hand, the adverse behavioral effects induced by DXM were reduced by LBP treatment. Histological results showed that LBP treatment alone did not promote hippocampal neurogenesis when compared to the normal control, but LBP could lessen the suppression of hippocampal neurogenesis induced by DXM. The findings provide insights for the potential use of wolfberry as an adjunct treatment option for alleviating mood disturbances during rehabilitation of cough syrup abusers.

    Topics: Animals; Antitussive Agents; Anxiety Disorders; Depressive Disorder; Dextromethorphan; Disease Models, Animal; Drugs, Chinese Herbal; Hippocampus; Male; Neurogenesis; Neurons; Neuroprotective Agents; Psychotropic Drugs; Random Allocation; Rats, Sprague-Dawley; Social Behavior; Substance-Related Disorders

2017
Dextromethorphan Exhibits Anti-inflammatory and Immunomodulatory Effects in a Murine Model of Collagen-Induced Arthritis and in Human Rheumatoid Arthritis.
    Scientific reports, 2017, 09-12, Volume: 7, Issue:1

    Dextromethorphan (d-3-methoxy-17-methylmorphinan, DXM) is a commonly used antitussive with a favorable safety profile. Previous studies have demonstrated that DXM has anti-inflammatory and immunomodulatory properties; however, the effect of DXM in rheumatoid arthritis (RA) remains unknown. Herein, we found that DXM treatment attenuated arthritis severity and proinflammatory cytokine expression levels, including TNF-α, IL-6, and IL-17A, in paw tissues of CIA mice. DXM treatment also reduced serum TNF-α, IL-6, and IL-17A levels of CIA mice and patients with RA. DXM further decreased the production of anti-CII IgG, IFN-γ, and IL-17A in collagen-reactive CD4

    Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Autoantibodies; Biomarkers; Collagen Type II; Cytokines; Dendritic Cells; Dextromethorphan; Disease Models, Animal; Humans; Immunologic Factors; Inflammation Mediators; Lymphocyte Activation; Male; Mice; T-Lymphocytes

2017
Dextromethorphan upregulates osteoblast and osteoclast activity but does not attenuate ovariectomy-induced osteoporosis.
    Life sciences, 2017, Mar-15, Volume: 173

    Study on the in vivo regulatory role of glutamate in osteoblast (OB) and osteoclast (OC) differentiation is less advanced. The present study investigated the effect of dextromethorphan (DXM), an N-methyl-d-aspartate receptors (NMDARs) antagonist, on osteoporosis development.. In order to examine the role of glutamate in bone metabolism, ovariectomized (Ovx) female Wistar rats were injected three times per week for 8weeks with either saline, or 15μg/kg of β-estrodiol, or DXM (40mg/kg) intraperitoneally. Serum samples were collected every two weeks for measuring osteocalcin and C-terminal telopeptide of type I collagen (CTX-1) level. Rats were then sacrificed at week 8 and the femurs harvested for micro-CT scanning and mechanical strength.. In saline-treated group, osteocalcin level significantly lower than that of sham-operated rats at 8weeks after operation, while CTX-1 levels were not affected. Estrogen treatment, as a positive control, partially inhibited the Ovx-induced reduction of osteocalcin serum level. DXM injection prevented the Ovx-induced reduction of osteocalcin expression and significantly upregulated CTX-1 expression. The micro-CT scan showed that the bone volume density decreased significantly in DXM treated rats compared to the sham-operated rats. In the mechanical strength assay, the maximum failure load for DXM treatment was significantly lower than the other groups.. Treatment with DXM upregulated OB and OC markers in Ovx rats, however with a greater effect on the OC marker, and had no significant benefit on bone volume density or bone strength.

    Topics: Animals; Bone Density; Collagen Type I; Dextromethorphan; Disease Models, Animal; Female; Osteoblasts; Osteoclasts; Osteoporosis; Ovariectomy; Peptide Fragments; Rats; Rats, Wistar

2017
Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation.
    Bioorganic & medicinal chemistry, 2015, Oct-01, Volume: 23, Issue:19

    3-Nitro-1H-1,2,4-triazole- and 2-nitro-1H-imidazole-based amides with an aryloxy-phenyl core were synthesized and evaluated as antitrypanosomal agents. All 3-nitrotriazole-based derivatives were extremely potent anti-Trypanosoma cruzi agents at sub nM concentrations and exhibited a high degree of selectivity for the parasite. The 2-nitroimidazole analogs were only moderately active against T. cruzi amastigotes and exhibited low selectivity. Both types of compound were active against Leishmania donovani axenic amastigotes with excellent selectivity for the parasite, whereas three 2-nitroimidazole-based analogs were also moderately active against infected macrophages. However, no compound demonstrated selective activity against Trypanosoma brucei rhodesiense. The most potent in vitro anti-T. cruzi compounds were tested in an acute murine model and reduced the parasites to an undetectable level after five days of treatment at 13 mg/kg/day. Such compounds are potential inhibitors of T. cruzi CYP51 and, being excellent substrates for the type I nitroreductase (NTR) which is specific to trypanosomatids, work as prodrugs and constitute a new generation of effective and more affordable antitrypanosomal agents.

    Topics: Animals; Binding Sites; Cell Line; Chagas Disease; Disease Models, Animal; Leishmania donovani; Mice; Mice, Inbred BALB C; Nitroreductases; Parasitic Sensitivity Tests; Prodrugs; Protein Structure, Tertiary; Protozoan Proteins; Rats; Sterol 14-Demethylase; Structure-Activity Relationship; Triazoles; Trypanocidal Agents; Trypanosoma brucei rhodesiense; Trypanosoma cruzi

2015
Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment.
    Nature medicine, 2015, Volume: 21, Issue:4

    In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.

    Topics: Adult; Animals; Calcium; Cell Line; Cell Survival; Dextromethorphan; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Design; Exenatide; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nerve Tissue Proteins; Pancreas; Peptides; Receptors, N-Methyl-D-Aspartate; Venoms

2015
Dual Therapeutic Effects of C-10068, a Dextromethorphan Derivative, Against Post-Traumatic Nonconvulsive Seizures and Neuroinflammation in a Rat Model of Penetrating Ballistic-Like Brain Injury.
    Journal of neurotrauma, 2015, Oct-15, Volume: 32, Issue:20

    Post-traumatic seizures can exacerbate injurious outcomes of severe brain trauma, yet effective treatments are limited owing to the complexity of the pathology underlying the concomitant occurrence of both events. In this study, we tested C-10068, a novel deuterium-containing analog of (+)-N-methyl-3-ethoxymorphinan, in a rat model of penetrating ballistic-like brain injury (PBBI) and evaluated the effects of C-10068 on PBBI-induced nonconvulsive seizures (NCS), acute neuroinflammation, and neurofunctional outcomes. NCS were detected by electroencephalographic monitoring. Neuroinflammation was evaluated by immunohistochemical markers, for example, glial fibrillary acidic protein and major histocompatibility complex class I, for activation of astrocytes and microglia, respectively. Neurofunction was tested using rotarod and Morris water maze tasks. Three infusion doses of C-10068 (1.0, 2.5, and 5.0 mg/kg/h × 72 h) were tested in the antiseizure study. Neuroinflammation and neurofunction were evaluated in animals treated with 5.0 mg/kg/h × 72 h C-10068. Compared to vehicle treatment, C-10068 dose dependently reduced PBBI-induced NCS incidence (40-50%), frequency (20-70%), and duration (30-82%). The most effective antiseizure dose of C-10068 (5.0 mg/kg/h × 72 h) also significantly attenuated hippocampal astrocyte activation and perilesional microglial reactivity post-PBBI. Within C-10068-treated animals, a positive correlation was observed in reduction in NCS frequency and reduction in hippocampal astrocyte activation. Further, C-10068 treatment significantly attenuated astrocyte activation in seizure-free animals. However, C-10068 failed to improve PBBI-induced motor and cognitive functions with the dosing regimen used in this study. Overall, the results indicating that C-10068 exerts both potent antiseizure and antiinflammatory effects are promising and warrant further investigation.

    Topics: Animals; Anti-Inflammatory Agents; Anticonvulsants; Astrocytes; Behavior, Animal; Dextromethorphan; Disease Models, Animal; Electroencephalography; Excitatory Amino Acid Antagonists; Head Injuries, Penetrating; Hippocampus; Inflammation; Male; Microglia; Rats; Rats, Sprague-Dawley; Seizures

2015
Involvement of AMPA receptors in the antidepressant-like effects of dextromethorphan in mice.
    Behavioural brain research, 2015, Dec-15, Volume: 295

    Dextromethorphan (DM) is an antitussive with rapid acting antidepressant potential based on pharmacodynamic similarities to ketamine. Building upon our previous finding that DM produces antidepressant-like effects in the mouse forced swim test (FST), the present study aimed to establish the antidepressant-like actions of DM in the tail suspension test (TST), another well-established model predictive of antidepressant efficacy. Additionally, using the TST and FST, we investigated the role of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in the antidepressant-like properties of DM because accumulating evidence suggests that AMPA receptors play an important role in the pathophysiology of depression and may contribute to the efficacy of antidepressant medications, including that of ketamine. We found that DM displays antidepressant-like effects in the TST similar to the conventional and fast acting antidepressants characterized by imipramine and ketamine, respectively. Moreover, decreasing the first-pass metabolism of DM by concomitant administration of quinidine (CYP2D6 inhibitor) potentiated antidepressant-like actions, implying DM itself has antidepressant efficacy. Finally, in both the TST and FST, pretreatment with the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide) significantly attenuated the antidepressant-like behavior elicited by DM. Together, the data show that DM exerts antidepressant-like actions through AMPA receptors, further suggesting DM may act as a safe and effective fast acting antidepressant drug.

    Topics: Animals; Antidepressive Agents; Behavior, Animal; Depression; Depressive Disorder; Dextromethorphan; Disease Models, Animal; Excitatory Amino Acid Antagonists; Hindlimb Suspension; Imipramine; Ketamine; Male; Mice; Quinidine; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Swimming

2015
Repeated, high-dose dextromethorphan treatment decreases neurogenesis and results in depression-like behavior in rats.
    Experimental brain research, 2015, Volume: 233, Issue:7

    Abuse of cough mixture is increasingly prevalent worldwide. Clinical studies showed that chronic consumption of cough mixture at high dosages may lead to psychiatric symptoms, especially affective disturbances, with the underlying mechanisms remain elusive. The present study aims at exploring the effect of repeated, high-dose dextromethorphan (DXM, a common active component of cough mixture) treatment on adult hippocampal neurogenesis, which is associated with pathophysiology of mood disturbances. After treatment with a high-dose of DXM (40 mg/kg/day) for 2 weeks, Sprague-Dawley rats showed increased depression-like behavior when compared to the control animals. Neurogenesis in the hippocampus was suppressed by DXM treatment, which was indicated by decreases in number of proliferative cells and doublecortin (an immature neuron marker)-positive new neurons. Furthermore, the dendritic complexity of the immature neurons was suppressed by DXM treatment. These findings suggest that DXM induces depression- and anxiety-like behavior and suppresses neurogenesis in rats. The current experimental paradigm may serve as an animal model for study on affective effect of cough mixture abuse, rehabilitation treatment options for abusers and the related neurological mechanisms.

    Topics: Animals; Body Weight; Bromodeoxyuridine; Cell Proliferation; Dendrites; Depression; Dextromethorphan; Disease Models, Animal; Dose-Response Relationship, Drug; Doublecortin Domain Proteins; Doublecortin Protein; Excitatory Amino Acid Antagonists; Exploratory Behavior; Hippocampus; Interpersonal Relations; Male; Microtubule-Associated Proteins; Neurogenesis; Neurons; Neuropeptides; Rats; Rats, Sprague-Dawley; Swimming; Time Factors

2015
Effects of dextromethorphan and oxycodone on treatment of neuropathic pain in mice.
    Journal of biomedical science, 2015, Sep-22, Volume: 22

    Neuropathic pain is a very troublesome and difficult pain to treat. Although opioids are the best analgesics for cancer and surgical pain in clinic, only oxycodone among opioids shows better efficacy to alleviate neuropathic pain. However, many side effects associated with the use of oxycodone render the continued use of it in neuropathic pain treatment undesirable. Hence, we explored whether dextromethorphan (DM, a known N-methyl-D-aspartate receptor antagonist with neuroprotective properties) could potentiate the anti-allodynic effect of oxycodone and underlying mechanisms regarding to glial cells (astrocytes and microglia) activation and proinflammatory cytokines release in a spinal nerve injury (SNL) mice model.. Oxycodone produced a dose-dependent anti-allodynic effect. Co-administration of DM at a dose of 10 mg/kg (i.p.) (DM10) which had no anti-allodynic effect by itself enhanced the acute oxycodone (1 mg/kg, s.c.) effect. When the chronic anti-allodynic effects were examined, co-administration of DM10 also significantly enhanced the oxycodone effect at 3 mg/kg. Furthermore, oxycodone decreased SNL-induced activation of glial cells (astrocytes and microglia) and plasma levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α). Co-administration of DM10 potentiated these effects of oxycodone.. The combined use of DM with oxycodone may have therapeutic potential for decreasing the effective dose of oxycodone on the treatment of neuropathic pain. Attenuation of the glial activation and proinflammatory cytokines in the spinal cord may be important mechanisms for these effects of DM.

    Topics: Animals; Astrocytes; Cytokines; Dextromethorphan; Disease Models, Animal; Drug Synergism; Male; Mice; Microglia; Neuralgia; Oxycodone

2015
Low doses of dextromethorphan have a beneficial effect in the treatment of neuropathic pain.
    Fundamental & clinical pharmacology, 2014, Volume: 28, Issue:6

    N-methyl-D-aspartate receptor (NMDAR) antagonists may be given in persistent neuropathic pain, but adverse events especially with ketamine may limit their clinical use. Less central and cognitive adverse events are described with dextromethorphan and memantine. These molecules have been explored in many preclinical and clinical studies, but data are conflicting as regards neuropathic pain alleviation. Dextromethorphan and memantine have been administered to animals after spinal nerve ligation (SNL) to evaluate their antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) residues in the NR2B NMDAR subunit. Spinal nerve ligation and sham animals received dextromethorphan (10 mg/kg, i.p.), memantine (20 mg/kg, i.p.) or saline (1 mL/kg, i.p.). These drugs were administered once symptoms of allodynia and hyperalgesia had developed. Tests were carried out before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were, respectively, evaluated by von Frey, Randall & Selitto and Y-maze tests and molecular events by Western blot analysis. Spinal nerve-ligated animals displayed nociception and impaired spatial memory. Dextromethorphan, but not memantine, reversed neuropathic pain (NP) symptoms, restored spatial memory integrity and decreased the expression of pTyr(1336)NR2B. Following postoperative administration of dextromethorphan, this study has demonstrated for the first time a concordance between behaviour, cognitive function and molecular events via pTyr(1336)NR2B for neuropathic pain alleviation. Confirmation of these findings in patients would constitute a major step forward in the treatment of neuropathic pain and in the improvement of cognitive function and quality of life.

    Topics: Animals; Cognition; Dextromethorphan; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hyperalgesia; Male; Maze Learning; Memantine; Neuralgia; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

2014
The common antitussive agent dextromethorphan protects against hyperoxia-induced cell death in established in vivo and in vitro models of neonatal brain injury.
    Neuroscience, 2014, Aug-22, Volume: 274

    Preterm infants are prematurely subjected to relatively high oxygen concentrations, even when supplemental oxygen is not administered. There is increasing evidence to show that an excess of oxygen is toxic to the developing brain. Dextromethorphan (DM), a frequently used antitussive agent with pleiotropic mechanisms of action, has been shown to be neuroprotective in various models of central nervous system pathology. Due to its numerous beneficial properties, it might also be able to counteract detrimental effects of a neonatal oxygen insult. The aim of the current study was to evaluate its therapeutic potential in established cell culture and rodent models of hyperoxia-induced neonatal brain injury. For in vitro studies pre- and immature oligodendroglial (OLN-93) cells were subjected to hyperoxic conditions for 48 h after pre-treatment with increasing doses of DM. For in vivo studies 6-day-old Wistar rat pups received a single intraperitoneal injection of DM in two different dosages prior to being exposed to hyperoxia for 24h. Cell viability and caspase-3 activation were assessed as outcome parameters at the end of exposure. DM significantly increased cell viability in immature oligodendroglial cells subjected to hyperoxia. In pre-oligodendroglial cells cell viability was not significantly affected by DM treatment. In vivo caspase-3 activation induced by hyperoxic exposure was significantly lower after administration of DM in gray and white matter areas. In control animals kept under normoxic conditions DM did not significantly influence caspase-3-dependent apoptosis. The present results indicate that DM is a promising and safe treatment strategy for neonatal hyperoxia-induced brain injury that merits further investigation.

    Topics: Animals; Animals, Newborn; Antitussive Agents; Apoptosis; Brain; Brain Injuries; Caspase 3; Cell Line; Cell Survival; Cytokines; Dextromethorphan; Disease Models, Animal; Dose-Response Relationship, Drug; Gray Matter; Hyperoxia; Neuroprotective Agents; Oligodendroglia; Oxygen; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Sigma-1 Receptor; White Matter

2014
Attenuating heat-induced acute lung inflammation and injury by dextromethorphan in rats.
    American journal of respiratory cell and molecular biology, 2012, Volume: 46, Issue:3

    Dextromethorphan (DM) has been shown to protect against endotoxic shock in mice. Heatstroke resembles sepsis in many respects. The objective of this study was to examine the heat-induced acute lung inflammation and injury in rats with or without DM, and for comparison with those of the rats with MK-801 (an N-methyl-D-aspartate receptor antagonist), SA4503 (a sigma-1 receptor agonist), or fluoxetine (a serotonin reuptake inhibitor). Heatstroke was induced by exposing the anesthetized rats to heat stress (43°C for 68 min). At 68 minutes after start of heat stress, animals treated with vehicle medium, DM (10-30 mg/kg of body weight, intramuscular), MK-801 (1 mg/kg of body weight, intraperitoneal), SA4503 (1 mg/kg of body weight, intraperitoneal), or fluoxetine (5 mg/kg of body weight, intraperitoneal) were allowed to recover at room temperature (26°C). As compared with vehicle-treated heatstroke rats (25-31 min; n = 8), DM (30 mg/kg)-treated heatstroke rats and MK-801 (1 mg/kg)-treated heatstroke rats had significantly greater survival time (193-209 min [n = 7] and 121-133 min [n = 8], respectively). However, the survival times for the SA4503-treated heatstroke rats (28-34 min; n = 8) or the fluoxetine-treated heatstroke rats (20-26 min; n = 8) were not significantly different from the vehicle-treated heatstroke rats. DM treatment significantly: (1) reduced acute lung injury, including edema, neutrophils infiltration, and hemorrhage scores; (2) decreased acute pleurisy; and (3) decreased bronchoalveolar fluid levels of the proinflammatory cytokines, and ischemia and oxidative damage markers during heatstroke. Our results indicate that DM therapy may improve outcomes of heatstroke in rats by antagonizing the N-methyl-D-aspartate receptors.

    Topics: Acute Lung Injury; Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Dextromethorphan; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluoxetine; Heat Stroke; Hemodynamics; Inflammation Mediators; Lung; Male; Piperazines; Pneumonia; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Time Factors

2012
Investigation of antitussive and toxicological activity of Ballota limbata in mice.
    Pharmaceutical biology, 2011, Volume: 49, Issue:6

    Ballota limbata Benth. (Lamiaceae) (syn, Otostegia limbata Hook.f.) is a species grown in the North West Frontier Province and the lower hills of West Punjab, Pakistan. Ballota species are renowned for their antispasmodic, antiulcer, diuretic, vermifuge, and especially sedative effects. However, little is known about the biological activity of B. limbata.. Evaluation of antitussive activity and safety profile of dried B. limbata extract.. Whole air-dried plants were partitioned with various solvents and the butanol fraction was subjected to antitussive evaluation using a sulfur dioxide (SO(2))-induced cough model in mice. Codeine and dextromethorphan were used as positive control. Safety profile of the testing material was established using standard toxicity tests.. B. limbata extract inhibited cough provoked by SO(2) gas in mice in a dose-dependent manner. The extract exhibited maximum protection against SO(2)-induced cough after 60 min of administration. B. limbata offered maximum cough suppressive effects, that is, number of coughs during 60 min was 11.66 ± 1.2 (mean ± SEM), after s.c. administration of 800 mg/kg, as compared with codeine 10 mg/kg, s.c., dextromethorphan 10 mg/kg, s.c., and saline showing a frequency of cough of 11.75 ± 1.18, 12.25 ± 0.83, and 46.25 ± 1.52, respectively. LD(50) value of B. limbata was greater than 5000 mg/kg. No sign of neural impairment was observed at antitussive doses and the extract has been well-tolerated at higher doses.. This study demonstrates that the extract of B. limbata has shown strong cough suppressive effect in mice without yielding any notable toxicity.

    Topics: Animals; Antitussive Agents; Ballota; Codeine; Cough; Dextromethorphan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Lethal Dose 50; Male; Medicine, Traditional; Mice; Mice, Inbred Strains; Pakistan; Phytotherapy; Plant Extracts

2011
Persistent cognitive deficits, induced by intrathecal methotrexate, are associated with elevated CSF concentrations of excitotoxic glutamate analogs and can be reversed by an NMDA antagonist.
    Behavioural brain research, 2011, Dec-01, Volume: 225, Issue:2

    For patients with acute lymphoblastic leukemia or non-Hodgkin lymphoma, intrathecal (IT) methotrexate (MTX) significantly reduces the risk of relapse within the central nervous system, but is associated with neurotoxic sequelae. We established a rat model of MTX-induced cognitive deficits to further investigate the underlying pathophysiology and to develop protective therapeutic interventions. IT MTX 0.5 mg/kg was administered to 10-week old male Long Evans rats. Cerebrospinal fluid (CSF) was collected for measurement of folate, homocysteine, and excitotoxic glutamate analogs. Recognition and spatial memory were tested in the novel object recognition (NOR) task and the object placement (OP) task, respectively. Four doses of IT MTX in a two-week period induced cognitive deficits persisting at least three months after the final injection. CSF concentrations of the excitotoxic glutamate analogs homocysteic acid and homocysteine sulfinic acid were increased relative to baseline for the same three-month period. Dextromethorphan, a noncompetitive antagonist at the N-methyl-D-aspartate receptor, administered at a dose of 2 mg/kg intraperitoneally twice daily for a total of four doses, improved cognitive function among the MTX-treated rats, with no effect on control rats. Although this improvement was transient, each repeated treatment with dextromethorphan was followed by normalization of cognitive function. In conclusion, IT MTX induces persistent alterations in glutaminergic tone that may contribute to persistent cognitive deficits. Treatment with a glutamate receptor antagonist such as dextromethorphan may ameliorate the negative cognitive outcomes observed among patients with leukemia or lymphoma treated with repeated doses of prophylactic IT MTX.

    Topics: Animals; Cognition Disorders; Dextromethorphan; Disease Models, Animal; Excitatory Amino Acid Antagonists; Folic Acid; Glutamic Acid; Homocysteine; Humans; Injections, Spinal; Male; Memory Disorders; Methotrexate; Rats; Rats, Long-Evans; Recognition, Psychology

2011
Coadministration of dextromethorphan during pregnancy and throughout lactation prevents morphine-induced hyperprolactinemia in female rats.
    Fertility and sterility, 2010, Mar-15, Volume: 93, Issue:5

    To investigate whether coadministration of dextromethorphan (DM) could suppress morphine-induced hyperprolactinemia in female rats during pregnancy and throughout lactation.. Controlled prospective study.. University research laboratory.. One hundred adult female Sprague-Dawley rats.. Rats were randomly divided into four groups and were subcutaneously injected with either saline, morphine, morphine + DM, or DM alone twice a day, progressively increasing by 1 mg/kg at 7-day intervals from an initial dose of 2 mg/kg for both morphine and DM. Drug administration was continued during pregnancy. After the offspring were born, the doses injected into the dams were increased by 1 mg/kg every 2 weeks.. Serum prolactin (PRL) concentration and dopamine turnover rate at the hypothalamus and pituitary.. Chronic morphine administration induced higher PRL concentrations than the control animals at mating, and at early and late pregnancy. In rats receiving DM coadministration, we did not observe any increase by morphine. Our neurochemical results showed that this effect of DM may be partly through blocking the effect of morphine on inhibition of tuberoinfundibular dopaminergic (TIDA) neuronal activity.. The use of DM as an adjuvant in females receiving chronic morphine treatment may prevent morphine-induced hyperprolactinemia.

    Topics: Animals; Dextromethorphan; Disease Models, Animal; Dopamine; Drug Administration Schedule; Female; Hyperprolactinemia; Hypothalamus; Injections, Subcutaneous; Lactation; Morphine; Pituitary Gland; Pregnancy; Prolactin; Rats; Rats, Sprague-Dawley; Time Factors; Up-Regulation

2010
Evaluation of the analgesic effect of dextromethorphan and its interaction with nitric oxide on sciatic nerve ligated rats.
    Journal of acupuncture and meridian studies, 2010, Volume: 3, Issue:1

    The symptoms of neuropathic pain are often intractable because they are poorly relieved by conventional analgesics. This therapeutic area remains one of the least satisfactorily managed by current drugs. Effective therapy for this type of pain is lacking, and the underlying mechanisms are poorly understood. The present study was undertaken to determine the effect of sciatic nerve ligation on inducing neuropathic pain and to understand the mechanisms involved, and the effect of, an L-nitro-arginine methyl ester (L-NAME)/dextromethorphan combination therapy on reducing neuropathic pain. According to our results, L-NAME and dextromethorphan showed analgesic properties, but only 100 mg/kg L-NAME had an additive effect on the analgesic effects of dextromethorphan. Our observations support the idea that N-methyl-D-aspartate/nitric oxide pathways play an important role in the development of such sciatic nerve ligated-evoked pathological pain conditions, thus this combination therapy could be used instead of conventional treatment.

    Topics: Analgesics; Animals; Dextromethorphan; Disease Models, Animal; Drug Interactions; Humans; Ligation; Male; Nitric Oxide; Rats; Sciatic Nerve; Sciatica

2010
Dextromethorphan reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice.
    Cardiovascular research, 2009, Apr-01, Volume: 82, Issue:1

    Macrophage-related oxidative stress plays an important role in the inflammatory process in atherosclerosis. Recently, dextromethorphan (DXM), a common cough-suppressing ingredient with a high safety profile, was found to inhibit the activation of microglia, the resident macrophage in the nervous system. We investigated whether DXM could reduce macrophage production of cytokines and superoxide and the resultant influence on atherosclerosis formation in mice.. We used in vitro and in vivo studies to evaluate the DXM inhibitory effect on oxidative stress. Dextromethorphan pretreatment significantly suppressed the production of tumour necrosis factor-alpha, monocyte chemoattractant protein-1, interleukin-6, interleukin-10, and superoxide in macrophage cell culture after stimulation. Indeed, DXM reduced macrophage nicotinamide adenine dinucleotide phosphate oxidase activity by decreasing membrane translocation of p47(phox) and p67(phox) through the inhibition of protein kinase C and extracellular signal-regulated kinase activation. The anti-atherosclerosis effect of DXM was tested using two animal models, apolipoprotein E (apoE)-deficient mice and a mouse carotid ligation model. Dextromethorphan treatment (10-40 mg/kg/day) for 10 weeks in apoE-deficient mice significantly reduced superoxide production in their polymorphonuclear leukocytes and aortas. It significantly decreased the severity of aortic atherosclerosis in the apoE-deficient mice and decreased carotid neointima formation after ligation in C57BL/6 mice.. Our data show that DXM, with its novel effect in reducing oxidative stress, significantly reduces atherosclerosis and neointima formation in mice.

    Topics: Animals; Antioxidants; Apolipoproteins E; Atherosclerosis; Carotid Arteries; Carotid Artery Injuries; Cell Line, Tumor; Cell Proliferation; Cytokines; Dextromethorphan; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Humans; Hyperplasia; Ligation; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; NADPH Oxidases; Oxidative Stress; Phosphoproteins; Protein Kinase C; Protein Transport; Superoxides; Tunica Intima

2009
Dextromethorphan is protective against sensitized N-methyl-D-aspartate receptor-mediated excitotoxic brain damage in the developing mouse brain.
    The European journal of neuroscience, 2008, Volume: 27, Issue:4

    Enhanced glutamate release and inflammation play an important role in the pathogenesis of developmental brain injury. Although N-methyl-d-aspartate receptor (NMDAR) antagonists potently attenuate neonatal brain damage in several animal models, they can also impact trophic functions in the developing brain. As a consequence, high-affinity NMDAR antagonists have been shown to trigger widespread apoptotic neurodegeneration in the newborn brain. Dextromethorphan (DM), a low-affinity NMDAR antagonist with anti-inflammatory properties, may be neuroprotective against excitotoxic and inflammation-enhanced excitotoxic brain injury, without the associated stimulation of apoptotic degeneration. Using an established newborn mouse model of excitotoxic brain damage, we determined whether systemic injection of DM significantly attenuates excitotoxic lesion size. We investigated several doses and time regimens; a dose of 5 microg/g DM given in a combination of both pre-injury and repetitive post-injury treatment proved most effective. DM treatment significantly reduced lesion size in gray and white matter by reducing cell death as shown by a decreased Fluoro-Jade B staining and caspase-3 activation. Pre-treatment with interleukin-1beta and lipopolysaccharide enhanced NMDAR-mediated excitotoxic brain injury and microglial cell activation. This sensitizing effect was abolished by DM treatment, as the effectiveness of DM in reducing lesion size and microglial cell activation was similar to phosphate-buffered saline-pre-treated controls. In all cases, no gender-specific differences were detected. DM treatment did not trigger any apoptotic neurodegeneration (caspase-3 cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Fluoro-Jade B staining). Although functional parameters were not measured, our data corroborate reports that DM is neuroprotective and that it may therefore improve functional outcome following perinatal brain injury.

    Topics: Animals; Animals, Newborn; Apoptosis; Brain; Caspase 3; Dextromethorphan; Disease Models, Animal; Encephalomalacia; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Ibotenic Acid; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Male; Mice; Microglia; Neuroprotective Agents; Polymerase Chain Reaction; Receptors, N-Methyl-D-Aspartate

2008
Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias.
    Neuroreport, 2008, Jan-08, Volume: 19, Issue:1

    Levodopa (L-DOPA) is the 'gold standard' to treat Parkinson's disease. Unfortunately, dyskinesias detract from its efficacy. Current dyskinesia treatments, including amantadine and dextromethorphan, are thought to work via N-methyl-D-aspartate (NMDA) antagonism, but this hypothesis has not been tested. The NMDA antagonists MK-801 and HA-966 failed to suppress expression of dyskinesias in the 6-hydroxydopamine rat. Dyskinesias, however, were suppressed by the NMDA and sigma (sigma)-1 receptor ligand dextromethorphan and by the sigma-1 antagonist BMY-14802. Antidyskinetic effects of dextromethorphan may be mediated via mechanisms other than NMDA, including the sigma-1 receptor and other binding sites common to dextromethorphan and BMY-14802.

    Topics: Adrenergic Agents; Amphetamine; Animals; Anti-Anxiety Agents; Behavior, Animal; Dextromethorphan; Disease Models, Animal; Dopamine Agents; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Levodopa; Ligands; Male; N-Methylaspartate; Neurotoxicity Syndromes; Oxidopamine; Pyrimidines; Rats; Rats, Sprague-Dawley; Time Factors

2008
Alterations of postsynaptic density proteins in the hippocampus of rat offspring from the morphine-addicted mother: Beneficial effect of dextromethorphan.
    Hippocampus, 2006, Volume: 16, Issue:6

    Infants passively exposed to morphine or heroin through their addicted mothers usually develop characteristic withdrawal syndrome of morphine after birth. In such early life, the central nervous system exhibits significant plasticity and can be altered by various prenatal influences, including prenatal morphine exposure. Here we studied the effects of prenatal morphine exposure on postsynaptic density protein 95 (PSD-95), an important cytoskeletal specialization involved in the anchoring of the NMDAR and neuronal nitric oxide synthase (nNOS), of the hippocampal CA1 subregion from young offspring at postnatal day 14 (P14). We also evaluated the therapeutic efficacy of dextromethorphan, a widely used antitussive drug with noncompetitive antagonistic effects on NMDARs, for such offspring. The results revealed that prenatal morphine exposure caused a maximal decrease in PSD-95 expression at P14 followed by an age-dependent improvement. In addition, prenatal morphine exposure reduced not only the expression of nNOS and the phosphorylation of cAMP responsive element-binding protein at serine 133 (CREB(Serine-133)), but also the magnitude of long-term depression (LTD) at P14. Subsequently, the morphine-treated offspring exhibited impaired performance in long-term learning and memory at later ages (P28-29). Prenatal coadministration of dextromethorphan with morphine during pregnancy and throughout lactation could significantly attenuate the adverse effects as described above. Collectively, the study demonstrates that maternal exposure to morphine decreases the magnitude of PSD-95, nNOS, the phosphorylation of CREB(Serine-133), and LTD expression in hippocampal CA1 subregion of young offspring (e.g., P14). Such alterations within the developing brain may play a role for subsequent neurological impairments (e.g., impaired performance of long-term learning and memory). The results raise a possibility that postsynaptic density proteins could serve an important role, at least in part, for the neurobiological pathogenesis in offspring from the morphine-addicted mother and provide tentative therapeutic strategy.

    Topics: Animals; Animals, Newborn; Cyclic AMP Response Element-Binding Protein; Dextromethorphan; Disease Models, Animal; Disks Large Homolog 4 Protein; Excitatory Amino Acid Antagonists; Female; Hippocampus; Intracellular Signaling Peptides and Proteins; Long-Term Synaptic Depression; Membrane Proteins; Morphine; Morphine Dependence; Narcotics; Neuronal Plasticity; Nitric Oxide Synthase Type I; Organ Culture Techniques; Phosphorylation; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptic Membranes

2006
Dextromethorphan protects male but not female mice with brain ischemia.
    Neuroreport, 2006, Aug-21, Volume: 17, Issue:12

    The non-competitive N-methyl-D-aspartate receptor antagonist dextromethorphan is protective against some types of brain injury. Unilateral carotid ligation in postnatal day 12 CD1 mice produces ischemic brain injury. To evaluate the neuroprotective potential of dextromethorphan against ischemic injury in the immature brain, seven litters of postnatal day 12 CD1 mice received either dextromethorphan or vehicle after a unilateral carotid ligation. Only the male pups were protected, and brain injury was unchanged in the female pups treated with dextromethorphan. These results suggest that dextromethorphan neuroprotection against ischemic injury in the immature brain is sex-dependent.

    Topics: Animals; Animals, Newborn; Brain Ischemia; Dextromethorphan; Disease Models, Animal; Female; Male; Mice; Neuroprotective Agents; Severity of Illness Index; Sex Factors

2006
Treatment of pseudobulbar affect in ALS.
    The Lancet. Neurology, 2005, Volume: 4, Issue:5

    Topics: Amyotrophic Lateral Sclerosis; Animals; Brain Chemistry; Dextromethorphan; Disease Models, Animal; Drug Combinations; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Humans; Pseudobulbar Palsy; Quinidine; Serotonin

2005
The antitussive activity of delta-opioid receptor stimulation in guinea pigs.
    The Journal of pharmacology and experimental therapeutics, 2000, Volume: 292, Issue:2

    In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor.

    Topics: Animals; Carbazoles; Cell Line; CHO Cells; Cloning, Organism; Codeine; Cough; Cricetinae; Dextromethorphan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Guinea Pigs; Humans; Hydrocodone; Levallorphan; Male; Naloxone; Narcotic Antagonists; Protein Binding; Pyridines; Pyrroles; Pyrrolidines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

2000
Narrow beneficial effect of dextromethorphan on levodopa-induced motor response alterations in an experimental model of parkinsonism.
    Brain research, 1999, Aug-21, Volume: 839, Issue:1

    The effects of acute and chronic dextromethorphan on levodopa-induced motor response alterations have been studied in rats with unilateral lesion of nigrostriatal pathway induced by 6-hydroxydopamine (6-OHDA). Male Sprague-Dawley rats received a 6-OHDA injection (8 microg) into the left medial forebrain bundle. To validate the effect of acute dextromethorphan administration, groups of rats were treated with levodopa (25 mg/kg, twice daily) for 22 days. On day 23, animals received dextromethorphan (20, 30 or 40 mg/kg) immediately before levodopa. In a second set of experiments, lesioned rats were concomitantly treated with levodopa plus dextromethorphan (20, 30 or 40 mg/kg, twice at day) for 22 consecutive days in order to investigate the potential effect of chronic dextromethorphan administration in preventing the decrease in the duration of motor response. As expected, the duration of the motor response to levodopa had significantly decreased by the 22nd day of levodopa in each group of treatment. Acute administration of dextromethorphan on day 23 reversed the reduction in the duration of the levodopa response only when administered at the lowest dose used in the present study (20 mg/kg) (p<0.05). Chronic administration of dextromethorphan concomitant to levodopa did not prevent levodopa effect showing a significant decrease on motor response duration (124+/-4 on day 1 vs. 88+/-16 on day 22, p<0.05, 30 mg/kg, twice a day). Our results indicate that in parkinsonian rats dextromethorphan is not a useful drug to prevent levodopa-induced motor alterations, however, low doses of dextromethorphan may be beneficial to reverse these alterations in motor response.

    Topics: Animals; Antiparkinson Agents; Dextromethorphan; Disease Models, Animal; Excitatory Amino Acid Antagonists; Levodopa; Male; Motor Activity; Oxidopamine; Parkinson Disease, Secondary; Rats; Rats, Sprague-Dawley; Rotation; Treatment Outcome

1999
Dextromethorphan. Extrapolation of findings from reproductive studies in animals to humans.
    Canadian family physician Medecin de famille canadien, 1999, Volume: 45

    One of my patients, who is now 8 weeks pregnant, just read in the newspaper that dextromethorphan (DM), an antitussive found in a variety of cough medicines, caused birth defects in chicken embryos. The author of the study stated that even one dose could be dangerous and that he would never allow his wife to use this drug if she were pregnant. My patient was understandably very concerned because last week she was suffering from a nasty cough and had been advised by her pharmacist to use a cough mixture containing DM, which she subsequently took for several days.. You may reassure your patient that she did not put her baby at risk by using this substance. Dextromethorphan has been on the market for many years and has never been implicated as a human teratogen. Furthermore, chick embryos are not a good model for predicting teratogenic potential in humans and, consequently, were abandoned as such more than 30 years ago.

    Topics: Abnormalities, Drug-Induced; Animals; Antitussive Agents; Chick Embryo; Dextromethorphan; Disease Models, Animal; Female; Humans; Pregnancy; Risk Assessment; Teratogens; Toxicity Tests

1999
Dextromethorphan protects against cerebral injury following transient, but not permanent, focal ischemia in rats.
    Life sciences, 1997, Volume: 60, Issue:20

    Dextromethorphan (DM) has been observed to afford neuroprotection in a variety of in vitro and in vivo experimental models of CNS injury. We have evaluated the neuroprotective activity of DM following both transient (2 h) and permanent focal cerebral ischemia in the rat. Middle cerebral artery occlusion (MCAO) was produced in male Sprague-Dawley rats using the intraluminal filament technique. Animals were dosed s.c with 20 mg/kg DM at 0.5, 1, 2, 4, and 6 hours post occlusion. Analysis of brain injury was performed 24 hours after permanent occlusion or reperfusion. Following transient MCAO, vehicle treated rats exhibited a total infarct volume of 203 +/- 33 mm3. DM produced a 61% reduction in infarct volume to 79 +/- 13 mm3. Permanent MCAO produced a larger infarct volume (406 +/- 44 mm3) which was not significantly reduced in size by treatment with DM (313 +/- 58 mm3). Infarcted hemispheric oedema was not different in vehicle treated rats following transient or permanent MCAO and was not reduced by DM in either group. Following transient MCAO, rectal temperature was elevated 1,2 and 5 hours post occlusion. While not inducing hypothermia or altering physiological parameters such as blood pressure and blood gases, DM attenuated this injury-related increase in temperature, an effect which appeared to correlate with its ability to protect neurons in temperature regulating hypothalamic centres. The DM-induced reduction in infarction demonstrated in our model of transient focal cerebral ischemia provides further support for the in vivo neuroprotective activity of this compound. Importantly, these data demonstrate the limited neuroprotective efficacy of DM when attempting to combat more severe focal ischemic injuries and imply that drug-induced hypothermia is not ultimately responsible for its protective action.

    Topics: Animals; Brain Ischemia; Cerebral Infarction; Dextromethorphan; Disease Models, Animal; Hypothermia; Ischemic Attack, Transient; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury

1997
Neuroprotection by dextromethorphan in acute experimental subdural hematoma in the rat.
    Journal of neurotrauma, 1996, Volume: 13, Issue:2

    Experimental acute subdural hematoma in the rat has been shown to produce a zone of apparent infarction under the clot, and excitatory amino acid toxicity appears to play a role in the damage observed. We report the effect of dextromethorphan, a commonly used antitussive and a noncompetitive NMDA-type glutamate receptor antagonist, on the volume of histologic damage seen at 72 h after acute subdural hematoma in the rat. Sixty-five Long-Evans rats underwent placement of acute subdural hematoma using the "cranial window" model. Fourteen animals received oral dextromethorphan, 10 mg/kg/dose, twice daily for 3 days, and an additional 20 animals also received a single 20 mg/kg intraperitoneal dose 15 min after clot placement in addition to the oral regimen. Control animals received equal volumes of sterile water. Brain lesions in all animals were characterized by well-circumscribed infarctions underlying the subdural hematoma. Lesion volume in control animals was 88.3 +/- 9.3 mm3 (mean +/- standard error of the mean), while animals receiving dextromethorphan had significantly smaller lesions, which was independent of dosing schedule (59.9 +/- 9.2 mm3)(p = 0.0403). Animal weight was also found to be a significant covariate (p = 0.038). Because of its safety in humans and efficacy as a neuroprotectant in a variety of models, dextromethorphan may be a promising agent for clinical use, particularly in children.

    Topics: Animals; Dextromethorphan; Disease Models, Animal; Hematoma; Male; Rats; Subdural Space; Time Factors

1996
Dextromethorphan attenuates the effects of ischemia on rabbit electroretinographic oscillatory potentials.
    Documenta ophthalmologica. Advances in ophthalmology, 1993, Volume: 84, Issue:3

    Dextromethorphan has been shown to protect against ischemic tissue damage. We investigated the effects of dextromethorphan on electroretinographic oscillatory potentials in retinal ischemia. Retinal ischemia was induced in rabbits by increasing intraocular pressure to 120 mm Hg for 30, 60 or 90 minutes. Dextromethorphan was intravenously administered before ischemia and maintained throughout the whole period of experiments. Oscillatory potentials were recorded before and during ischemia as well as 4 hours of recirculation after ischemia. As expected, all oscillatory potentials were decreased after 60 and 90 minutes of ischemia. However, after 30 minutes of ischemia followed by 4 hours of recirculation, amplitudes of P2 were elevated whereas those of P3 and P4 were decreased with normal P1 amplitudes. Dextromethorphan administration diminished the effects of 30 minutes of ischemia on oscillatory potentials and partially attenuated the effects of 60 minutes of ischemia, whereas the effects of 90 minutes of ischemia could not be reversed by dextromethorphan treatment. These results indicate that electroretinographic oscillatory potentials could be useful indicators to evaluate retinal function in the ischemic condition and that dextromethorphan can attenuate the effects of relatively short periods of ischemia on rabbit electroretinographic oscillatory potentials.

    Topics: Acute Disease; Animals; Dextromethorphan; Disease Models, Animal; Electroretinography; Infusions, Intravenous; Intraocular Pressure; Ischemia; Perfusion; Rabbits; Retina; Retinal Vessels

1993
Dextromethorphan reduces neocortical ischemic neuronal damage in vivo.
    Brain research, 1988, Feb-09, Volume: 440, Issue:2

    The dextrorotatory morphinan dextromethorphan (DM), a clinically tested antagonist of the N-methyl-D-aspartate (NMDA) receptor-channel complex, was tested in an in vivo model of acute transient focal cerebral ischemia. Rabbits were randomly assigned to pretreatment with a 20 mg/kg i.v. bolus followed by 10 mg/kg/h of 0.4% DM in normal saline (NS), or with an equivalent volume of NS alone. They then underwent 1 h occlusion of the left internal carotid artery an anterior cerebral artery followed by 4 h of reperfusion. DM-treated animals showed a significant decrease in the percentage of severe neocortical ischemic neuronal damage (10.5%), as compared to NS-treated animals (49.6%).

    Topics: Animals; Cerebral Cortex; Dextromethorphan; Disease Models, Animal; In Vitro Techniques; Ischemic Attack, Transient; Levorphanol; Male; Rabbits

1988
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