Antitussive Effects of Memantine in Guinea Pigs

doi:10.1378/chest.11-0554

Chest

Volume 141, Issue 4, April 2012, Pages 996-1002

https://doi.org/10.1378/chest.11-0554 Get rights and content

Background

The treatment of cough is a significant clinical unmet need because there is little evidence that current therapies are effective. Based on evidence supporting a role for N-methyl d-aspartate receptors (NMDARs) in cough, we hypothesized that memantine, a low-affinity, uncompetitive NMDAR channel blocker in routine use for the treatment of Alzheimer disease, could be an effective, well-tolerated, antitussive therapy. The aim of this study was to establish preclinical evidence that memantine has antitussive effects.

Methods

We studied the influence of memantine on experimentally induced coughing in response to citric acid and bradykinin inhalation in guinea pigs. We also compared the potency and efficacy of memantine as an antitussive to other NMDAR antagonists, dextromethorphan and ketamine, and to the γ-aminobutyric acid class B receptor agonist baclofen.

Results

Compared with control subjects, 10 mg/kg memantine significantly reduced the cumulative number of coughs evoked by both citric acid (median, 24.0 [interquartile range (IQR), 13.0-25.5] vs 1.5 [IQR, 0.3-10.3] coughs; P = .012) and bradykinin aerosols (median, 16.0 [IQR, 9.5-18.5] vs 0.0 [IQR, 0-0.75] coughs; P = .002). Memantine 10 mg/kg produced a similar reduction in the cumulative number of coughs to baclofen 3 mg/kg and demonstrated comparatively greater cough suppression than 30 mg/kg dextromethorphan or 30 mg/kg ketamine. This dose of memantine produced no sedative or respiratory depressive effects.

Conclusions

This study illustrates that memantine has marked antitussive effects in guinea pigs, most likely mediated through NMDAR channel blockade. Memantine, therefore, has the potential to be a safe, effective, and well-tolerated antitussive agent.

Section snippets

Animals

Male Hartley guinea pigs (200-700 g) (Hilltop Lab Animals, Inc) were studied. All experiments were first approved by the institutional Animal Care and Use Committee.

Citric Acid-Induced Cough

Animals were placed in a transparent chamber (Buxco Research Systems) with a continuous flow of air and exposed to increasing concentrations of citric acid (0.01-0.3 mol/L) delivered by an ultrasonic nebulizer generating aerosol particles of 3 to 6 μm in diameter. Coughs were counted during a 5-min nebulization period and over the

Citric Acid-Induced Cough

Compared with vehicle, 10 mg/kg memantine markedly reduced the number of cumulative coughs evoked by 0.01 to 0.3 mol/L citric acid (P = .012) (Fig 1A, Table 1). At 1 and 3 mg/kg, there was no significant effect of memantine over vehicle. No side effects associated with the 10 mg/kg memantine treatment were apparent. As expected, tripling the dose of memantine to 30 mg/kg similarly reduced cough responses but produced signs of neurologic effects and slight sedation.

In contrast to 10 or 30 mg/kg

Discussion

To our knowledge, this study provides the first evidence that memantine has antitussive activity with significant inhibition of both citric acid- and bradykinin-induced cough in guinea pigs. The degree of inhibition was similar to that seen with baclofen but without the associated sedation and was comparably more effective than high doses of other NMDAR antagonists. Because there was little evidence of significant activity at nicotinic acetylcholine or serotonin receptors, it is most likely

Acknowledgments

Author contributions: Dr Canning had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Smith: contributed to the study design; acquisition, analysis, and interpretation of data; drafting and revisions of the manuscript; and approval of the final version of the manuscript.

Dr Hilton: contributed to the study design; acquisition, analysis, and interpretation of data; revisions of the manuscript; and approval

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To better address this hypothesis, we monitored heart rate, blood pressure and respiratory rate before and after systemic administration of Compound 801 or its vehicle in anesthetized guinea pigs (Fig. 5). We observed a profound reduction in mean arterial pressure and respiratory rate, with breathing patterns approximating that apparent following bilateral vagotomy and a decrease in blood pressure comparable to that achieved following autonomic ganglia blockade (Chou et al., 2008; Smith et al., 2012). Heart rate was minimally impacted by Compound 801.
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These include substance P on neurokinin 1 receptors (NK1), neurotrophins on tyrosine receptor kinase (Trk) receptors, and glutamate on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptors [55]. In the context of chronic cough, animal studies antagonising the NMDA receptor with memantine reduced cumulative coughs evoked by citric acid and bradykinin [94]. Translation to patients with chronic cough showed a median reduction in cough frequency of 17% but this was statistically non-significant and higher doses of memantine were not tolerated; 10 of the 14 subjects could not tolerate more than the starting dose of 10 mg [95].
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Memantine showed no psychotropic effects in animal and human studies [67,75–77]. In guinea pigs, memantine given intraperitoneally at a dose of 10 mg/kg reduced coughs evoked by citric acid and bradykinin aerosols, with a greater cough suppression than compared to dextrometorphan given at a dose of 30 mg/kg or to ketamine at a dose of 30 mg/kg [78]. In a follow-up study in guinea pigs with orally administered memantine, doses of 10 and 30 mg/kg reduced citric-acid induced coughs with comparable results from codeine administration at 30 mg/kg [79•].
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Funding/Support: This study was supported by a Medical Research Council Clinician Scientist Fellowship, a Medical Research Council Training Fellowship, and the National Institutes of Health [Grant HL083192].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

View full text

Chest

Original ResearchSigns and Symptoms of Chest DiseasesAntitussive Effects of Memantine in Guinea Pigs

Background

Methods

Results

Conclusions

Section snippets

Animals

Citric Acid-Induced Cough

Citric Acid-Induced Cough

Discussion

Acknowledgments

Neurosci Lett

Eur J Pharmacol

Brain Res

Chest

Curr Opin Pharmacol

Neurosci Lett

Pharmacol Biochem Behav

Neuron

Pulm Pharmacol Ther

Chest

Gastroenterology

Antitussive activity of sigma-1 receptor agonists in the guinea-pig

Br J Pharmacol

Comparison of the antitussive effects of codeine phosphate 20 mg, dextromethorphan 30 mg and noscapine 30 mg using citric acid-induced cough in normal subjects

Eur J Clin Pharmacol

The effect of inhaled and oral dextromethorphan on citric acid induced cough in man

Br J Clin Pharmacol

Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic cough

J Int Med Res

Objective evaluation of dextromethorphan and glaucine as antitussive agents

Br J Clin Pharmacol

Restricting cough and cold medicines in children

J Paediatr Child Health

Effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents

Arch Pediatr Adolesc Med

Original Research
Signs and Symptoms of Chest Diseases
Antitussive Effects of Memantine in Guinea Pigs