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2 Papers, 2 Opposing theories of Nicotine and SARS-CoV-2
Both of these papers were published this month and are particularly interested in the interaction between nicotine and Nicotinic acetylcholine receptors, or nAChRs, although the anti-nicotine hypothesis concerns itself as well with the neurological effects of COVID-19 as well as the ACE2 receptors and inflammation of endothelial cells.
Although I'm quite fascinated by this subject, I'm utterly unqualified to assess the merit of these papers. Maybe some scientifically-minded DUers who are interested in this topic will be able to make sense of this debate and share an insight or two.
1. Does COVID19 infect the brain? If so, smokers might be at a higher risk
N. Kabbani1, J.L. Olds2
1 School of Systems Biology, George Mason University, Fairfax, VA 22030
2SCHAR School of Public Policy, George Mason University, Arlington VA 22201
Now is the time to ask if infection with COVID19 can result in long-term neural damage in both
symptomatic and asymptomatic individuals and if chronic nicotine exposure through smoking
habits and addiction increases risk of developing COVID19 associated neuropathology through
interactions between nAChRs and ACE2 in neurons and glia.
Functional interaction between nicotine and components of the RAS (such as ACE2) are well
established in several organ systems including the lungs where smoking is found to impact
cardiopulmonary health (Ferrari et al., 2008; Virdis et al., 2010; R.M. et al., 2018). Similar RAS
components also exist in the human brain and nicotine exposure is documented to modulate RAS
activity in areas as the hypothalamus and brain stem leading to changes in endocrine release as
well as hypertension, respectively (Ferrari et al., 2007; J.M. et al., 2018). In the brain as
elsewhere ACE2 metabolizes angiotensin II to produce angiotensin 1-7 and this process occurs
in neurons as well as astrocytes (Hung et al., 2016). ACE2 signaling is widely thought to oppose
oxidative stress and neuroinflammation and disruption in ACE function and balance can drive
neurodegeneration of dopaminergic neurons(Labandeira-García et al., 2014). ACE activity may
also contribute to cortical cholinergic pathways and participate in the progression of Alzheimer’s
disease (Kehoe et al., 2009). Figure 1 depicts areas of notable ACE2 mRNA expression such as
the cortex, striatum, hypothalamus, and brainstem within the adult human brain as based on
microarray data from the Allen Brain Atlas (Jones et al., 2009). These regions, which are known
to also express various types of nAChRs (Dani and Bertrand, 2007) are putative sites for primary
infection with COVID19 in the human brain. Interactions between nAChRs and ACE2 have been
studied in several of these regions including the ventrolateral medulla (Deng et al., 2019), and
smoking may lead to enhanced viral infection through the ability of nicotine to upregulate
nAChRs in regions such as the lungs (Plummer et al., 2005; Thorgeirsson et al., 2008;
Changeux, 2010). In this case, upregulation of nAChRs in either/both neurons and astrocytes
could promote greater viral entry and replication through augmented ACE2 expression in the cell
(Fig. 2A).
symptomatic and asymptomatic individuals and if chronic nicotine exposure through smoking
habits and addiction increases risk of developing COVID19 associated neuropathology through
interactions between nAChRs and ACE2 in neurons and glia.
Functional interaction between nicotine and components of the RAS (such as ACE2) are well
established in several organ systems including the lungs where smoking is found to impact
cardiopulmonary health (Ferrari et al., 2008; Virdis et al., 2010; R.M. et al., 2018). Similar RAS
components also exist in the human brain and nicotine exposure is documented to modulate RAS
activity in areas as the hypothalamus and brain stem leading to changes in endocrine release as
well as hypertension, respectively (Ferrari et al., 2007; J.M. et al., 2018). In the brain as
elsewhere ACE2 metabolizes angiotensin II to produce angiotensin 1-7 and this process occurs
in neurons as well as astrocytes (Hung et al., 2016). ACE2 signaling is widely thought to oppose
oxidative stress and neuroinflammation and disruption in ACE function and balance can drive
neurodegeneration of dopaminergic neurons(Labandeira-García et al., 2014). ACE activity may
also contribute to cortical cholinergic pathways and participate in the progression of Alzheimer’s
disease (Kehoe et al., 2009). Figure 1 depicts areas of notable ACE2 mRNA expression such as
the cortex, striatum, hypothalamus, and brainstem within the adult human brain as based on
microarray data from the Allen Brain Atlas (Jones et al., 2009). These regions, which are known
to also express various types of nAChRs (Dani and Bertrand, 2007) are putative sites for primary
infection with COVID19 in the human brain. Interactions between nAChRs and ACE2 have been
studied in several of these regions including the ventrolateral medulla (Deng et al., 2019), and
smoking may lead to enhanced viral infection through the ability of nicotine to upregulate
nAChRs in regions such as the lungs (Plummer et al., 2005; Thorgeirsson et al., 2008;
Changeux, 2010). In this case, upregulation of nAChRs in either/both neurons and astrocytes
could promote greater viral entry and replication through augmented ACE2 expression in the cell
(Fig. 2A).
Link: http://molpharm.aspetjournals.org/content/molpharm/early/2020/04/01/molpharm.120.000014.full.pdf
2. A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications
jean-pierre CHANGEUX, Zahir Amoura1, Felix Rey2, Makoto Miyara1
Assistance Publique – Hôpitaux de Paris, Paris, France
Pasteur Institute, Paris, France
Nicotine may be suggested as a potential preventive agent against Covid-19 infection. Both the epidemiological/clinical evidence and the in silico findings may suggest that Covid-19 infection is a nAChR disease that could be prevented and may be controlled by nicotine. Nicotine would then sterically or allosterically compete with the SARS-CoV-2 binding to the nAChR. This legitimates the use of nicotine as a protective agent against SARS-CoV-2 infection and the subsequent deficits it causes in the CNS. Thus, in order to prevent the infection and the retro-propagation of the virus through the CNS, we plan a therapeutic assay against Covid-19 with nicotine (and other nicotinic agents) patches or other delivery methods (like sniffing/chewing) in hospitalized patients and in the general population.
In conclusion, we propose, and try to justify, the hypothesis that nAChRs play a critical role in the pathophysiology of SARS-CoV-2 infection and as a consequence propose nicotine and nicotinic orthosteric and/or allosteric agents as a possible therapy for SARS-CoV-2 infection. Interestingly, ivermectin, which has been recently shown to inhibit the replication of SARS-CoV-2 in cells in vitro [53], is a positive allosteric modulator of a7 nAChR [54]. The nicotinic hypothesis might be further challenged by additional clinical studies and by experimental observations determining whether SARS-CoV-2 physically interacts with the nAChR in vitro, for instance by electrophysiological recordings, high resolution EM and by animal model studies. Further work should also specify the still enigmatic relationships between ACE2 and nAChRs in the nervous system.
In conclusion, we propose, and try to justify, the hypothesis that nAChRs play a critical role in the pathophysiology of SARS-CoV-2 infection and as a consequence propose nicotine and nicotinic orthosteric and/or allosteric agents as a possible therapy for SARS-CoV-2 infection. Interestingly, ivermectin, which has been recently shown to inhibit the replication of SARS-CoV-2 in cells in vitro [53], is a positive allosteric modulator of a7 nAChR [54]. The nicotinic hypothesis might be further challenged by additional clinical studies and by experimental observations determining whether SARS-CoV-2 physically interacts with the nAChR in vitro, for instance by electrophysiological recordings, high resolution EM and by animal model studies. Further work should also specify the still enigmatic relationships between ACE2 and nAChRs in the nervous system.
Link: https://www.qeios.com/read/article/581
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