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Repurposing Memantine as a Nicotine Drug Alternative for a New COVID‐19 Host Receptor Site

(This article is a letter to the editor medical journal submission.)

The emerging “Nicotinic Hypothesis” proposes the COVID-19 entry point through acetylcholine receptors, (nAChRs), instead of the originally proposed angiotensin-converting enzyme 2 (ACE2) [1]. nAChRs, as entirely different receptor sites, are found both in the lung epithelium and olfactory system. Nicotine is being considered as a COVID-19 drug in this emerging hypothesis.[2]

For the enhancement of patient safety, memantine, also with primary acetylcholine and NMDA mechanisms, is being proposed as an alternative COVID-19 drug. To be clear, while nicotine and memantine are both NDMA antagonists, one can question, whether a nicotinic acetylcholine antagonist like memantine can still provide nicotinic acetylcholine protection, as does nicotine, a true nicotinic acetylcholine agonist. It remains to be seen whether this non-competitive memantine action can strengthen and cause greater nicotinic acetylcholine receptor density, this is perhaps a secondary explanation for its demonstrated neuroprotection. [30]

My reasoning is that memantine might be better tolerated than nicotine, especially considering the cardiovascular and respiratory stress connected with this disease. [3] In clinical trials, 4% experienced hypertension as compared to 2% receiving placebo. [4] Similarly, administering nicotine to a hypertensive non-smoker or cardiovascular disease might not result in an ideal disease outcome. While nicotine patches are safer than cigarettes, understandably very limited data on the use of nicotine replacement therapy with non-smokers. No prior data exists on non-smoker nicotine therapy while undergoing serious viral respiratory tract infection. Likewise, as nicotine can be a drug of abuse, perhaps, if we had a non-addictive replacement compound for a nonsmoker, this would offer a more advisable option.

While China has experienced low death rates, our attention is focusing on China with one-third worldwide smokers, and yet low numbers of COVID-19 cases. [5] Similarly, South Korea and France are experiencing low infection rates amongst their respective high smoking populations. [6,7] Understanding, nicotine-based coronavirus therapy goes back to a 2007 plant lectin study. This previous study discovered 33 plant lectins possessing antiviral activity against (SARS-CoV). [8] From amongst these 33 plant lectins, only two were not mannose-binding plant lectins. These two plants were stinging nettle (Urtica dioica), and the tobacco plant (Nicotiana tabacum). Stinging nettle contains acetylcholine, increasing acetylcholine expression upon ingestion. [9] We also find it to be neuroprotective against N-methyl-D-aspartate (NMDA) and SARS-CoV in rodent studies. [10,11]

Before discussing memantine as a therapeutic, it’s important to understand why researchers are strongly researching nicotine. Powerful evidence exists supporting neuroinvasiveness of COVID-19, as tested with previous coronaviruses. [12,13] We know Alzheimer’s patients experience olfactory dysfunction as an early symptom, as COVID-19 patients are likewise reporting. [14] Notwithstanding noted safety concerns, nicotine studies are supporting the use of nicotine therapy for the early stages of degenerative cognitive disorders. [15,16] Nicotine imitates the activity of acetylcholine, binding to the nicotinic acetylcholine receptor site, and thus increasing receptor site density. [17]

Studies are showing nicotine to increase ACE2 expression in the ACE/ANG II/AT1R arm. Nicotine increases the expression and/or activity of renin, ACE, and AT1R. In the offsetting ACE2/ANG-(1–7)/MasR arm, nicotine down-regulates the expression and/or action of ACE2 and AT2R. Hypothetically, this leads us to analyze the role of acetylcholine receptors in ACE2 regulation. And only now are we beginning to evaluate this mechanism within the context of viral neuroinfections. [18] As previously mentioned, as a nicotinic acetylcholine agonist, nicotine is being tested as a therapeutic in the form of nicotine transdermal patches in France. [2] In fact, the initial findings are so exciting, the French government is ordering a halt to the sale of all nicotine patches out of fears of low supply. Their theory proposes the possibility of inhibition of SARS-CoV-2 on the AChR through modulation of the ACE2 — nAChR interaction. This could be effective in promoting anti-viral activity in the olfactory system and lung epithelium earlier than other anti-cytokine therapies. [2]

Memantine is a drug used to treat moderate-to-severe confusion (dementia) related to Alzheimer’s disease. The drug carries shared mechanisms of action towards the “French Nicotine Hypothesis” target sites. [19] Its mechanism is neuroprotection, as is nicotine, for its (NMDA) mechanism. [20,21] We find a similar neuroprotective mechanism with agmatine, a metabolite of the amino acid arginine. [22] Agmatine is a potential non-Rx therapeutic alternative to memantine for the small subset of cases still experiencing hypertensive side effects. [23,24,25,26]

Adamantanes are a class of antiviral medications effective against influenza A but not influenza B viruses. [27] A previous letter to the editor was suggesting memantine as an antiviral, with adamantanes, such as amantadine, rimantadine, and bananin because of responsiveness with previous coronavirus infections. [28] A previous respiratory coronavirus study on rodents supports the use of the novel antiviral action of memantine on viral replication while improving neurological symptoms in virally implicated neurological infections. As potential viral adaptations, mutations in the surface spike (S) protein of human respiratory coronavirus OC43 appear after central nervous system cellular infection. [29]

Other primary memantine targets are the α7 and α4β2 nicotinic acetylcholine receptors and the 5-HT3 receptor systems. We believe these targets to play a role in modulating CNS functions, including learning and memory. [30] Smoking cessation models show the same targets with nicotine. [31] Accounting for 95% of all cellular nAChR in the brain, α4β2, and α7 nAChRs, are the two major nAChR subtypes.

Much as we see with nicotine, an emerging model for degenerative cognitive disorders, such as Alzheimer’s disease, is an imbalance within the renin-angiotensin system (RAS). [32,33] We see a further link in ACE2 dysfunction and speeding up the deterioration of cognitive function. [34,35,36] We are only recently finding the connections between the RAS and the cognitive function in the mechanisms and targets of neuroprotection. [37] We use memantine as a front-line medication for delaying loss of cognitive function. [38] Preliminary studies reviewed the actions of memantine on ACE2 and RAS. [39,40] While a newer compound compared to nicotine, memantine will be the subject of further investigations and reviews, as we must continue this initial work.

COVID-19 appears to pose the same neuro-invasive threat as previous respiratory coronaviruses, influencing subsequent respiratory failure. [12,13] To echo conclusions we read in the original “Nicotinic Hypothesis”, we must further uncover the “enigmatic relationships between ACE2 — nAChR in the nervous system.” The neuroprotection of memantine, along with host receptor site protection both ACE2 — nAChR, appears worthy of deeper consideration. As a safe, well-tolerated, non-toxic, and cost-effective COVID-19 therapeutic, memantine once again presents itself as a serious candidate for drug repurposing.

CONFLICT OF INTERESTS

The author declares that there is no conflict of interest. Funding was not sought for this publication. There is no third party support, including that from the pharmaceutical industry.

“Originally published on Optimize Better and submitted as a letter to the editor of a medical journal.”