J Taibah Univ Med Sci. 2020 Dec; 15(6): 550–553.
Determining the relationship between SARS-CoV-2 infection, dopamine, and COVID-19 complications
Muad M. Khalefah, Master of Science in Medicinea and Ayman M. Khalifah, MHPEdb,∗
There is compelling evidence that aged, immunosuppressed, and chronically ill patients are a high-risk group for increased mortality upon infection with the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study investigated the contribution of morbidities and related prescribed medications to COVID-19 associated mortality.
Based on the various recently reported clinical scenarios a theoretical framework was designed to shed light on the mode of infection of the central nervous system by SARS-CoV-2 and possible management options.
Dopamine-release mechanisms in the central nervous system may play a major role in the entry and propagation of coronaviruses.
This study emphasizes the need for a thorough and urgent investigation of the dopamine-release pathways in the central nervous system. These efforts will help find a definitive cure for the pandemic coronavirus disease (COVID-19).
J Med Virol. 2020 Apr 8 : 10.1002/jmv.25826.
An alteration of the dopamine synthetic pathway is possibly involved in the pathophysiology of COVID‐19
Serge Natafcorresponding author 1 , 2 , 3
To the Editor,
I have read with great interest the paper by Li et al 1 entitled “The neuroinvasive potential of SARS‐CoV2 may be at least partially responsible for the respiratory failure of COVID‐19 patients.” I would like here to provide arguments indicating that an alteration of the dopamine synthetic pathways is possibly involved in the pathophysiology of COVID‐19. A simple bioinformatics approach to predict new roles for any given gene consists in identifying the coexpression network it integrates with. To unravel putative neural impacts of SARS‐CoV2 infections, such a “culprit‐by‐association” strategy may be applied to Angiotensin I Converting Enzyme 2 (ACE2), the gene encoding the main receptor to SARS‐CoV2, SARS‐CoV, and MERS‐CoV. To this aim, multiexperiment matrix (MEM) 2 is a robust web tool allowing to combine and integrate correlation links between messenger RNA (mRNA) levels across a large number of human microarray datasets (precisely 2811). Surprisingly, according to MEM, the gene exhibiting the most statistically significant coexpression link with ACE2 is Dopa Decarboxylase (DDC) (P: 2.39E‐61; Pearson correlation test). Based on the hypothesis put forward by Li et al 1 , this observation is possibly interesting for several reasons. DDC is indeed a major enzyme of both the dopamine and the serotonin synthetic pathways as it converts L‐3,4‐dihydroxyphenylalanine (L‐DOPA) into dopamine and L‐5‐hydroxytryptophan into serotonin. In addition, DDC also supports the conversion of histidine into histamine. That ACE2 coregulates with DDC indicates a possible functional link between the ACE2‐mediated synthesis of angiotensin 1‐7 and the DDC‐mediated synthesis of dopamine and serotonin. Arguing for the existence of such a link, brain dopamine contents were shown to be increased following infusion of angiotensin 1‐7 in the hypothalamus of rats. 3 Along this line, angiotensin 1‐7 was shown to stimulate the renal synthesis of dopamine. 4 Conversely, that ACE2 coregulates with DDC also implies that any SARS‐CoV2‐induced downregulation of ACE2 expression, a process previously demonstrated for SARS‐CoV, 5 might be paralleled by alterations of both the dopamine and serotonin synthetic pathways. Supporting this view, ACE2 knockout (KO) mice were reported to exhibit dramatically low serotonin levels in both the blood and brain. 6 Dopamine levels were not assessed in this study but should be explored in future studies. While patients with COVID‐19 might suffer from of a central autonomic failure of respiratory functions, it is important to keep in mind that ACE2 and DDC may coexpress and coregulate in nonneuronal cell types. Indeed, among the microarray datasets compiled in MEM, the most significant correlations between ACE2 and DDC mRNA levels are found in studies exploring colorectal adenocarcinoma samples. Confirming this observation, a survey of the database “Human Protein Atlas,” the currently largest protein expression atlas of normal human tissues, shows that ACE2 and DDC are both highly expressed in intestinal epithelial cells. Since intestinal epithelial cells were shown to convert L‐DOPA into dopamine 6 and to provide an important source of blood‐circulating dopamine, 7 one may hypothesize that a defective expression of ACE2 and DDC in intestinal cells may translate into altered levels and/or regulation of dopamine in the blood of patients with COVID‐19. This is all the more interesting as experiments performed in mice demonstrate that dopamine may shape lung immunity via dopamine receptors expressed by alveolar epithelial cells, 8 lung macrophages, 8 and lung terminal nerves. 9 In particular, in a murine model of endotoxin‐induced acute lung injury, the dopamine D1 receptor agonist fenoldopam was shown to dampen inflammation as well as lung permeability and pulmonary edema. 8 The potential protective role of dopamine in the context of viral infections has been poorly investigated until now. In this regard, it is worth noting that in a recent work, DDC was found to negatively regulate the replication of the Flaviviridae viruses dengue and hepatitis C. 10 Experimental research works are needed to clarify the links between ACE2 and DDC during SARS‐CoV2 infection. Moreover, in patients suffering from severe forms of COVID‐19, the hypothesis of a systemic failure of the dopamine synthetic pathway should be taken into account and further explored.
Eur J Psychiatry. 2021 January-March; 35(1): 62–63.
Are dopamine and serotonin involved in COVID-19 pathophysiology?
- Attademoa,* and F. Bernardinib
The whole world is being affected by COVID-19 caused by SARS-CoV-2, with unprecedented consequences on health, social and economic systems in all countries.
The COVID-19 pandemic is not only a threat to physical health but mental health as well.1 In fact, scientific evidence is emerging on the potential direct effects of COVID-19 on mental health of people infected, as well as on the psychological impact on people quarantined, on patients with psychiatric disorders and on the health-care workforce.1, 2
Discussion on the first of these points (i.e. the direct effects of the infection on mental health) appears to be rather interesting. Clinical evidence is showing that patients with COVID-19 might experience short- and long-term mental health problems. Delirium, confusion, agitation, and altered consciousness, as well as depression, anxiety, traumatic stress, and insomnia, have been described not rarely in patients with COVID-19.1, 2
Putative aetiological mechanisms of the neuropsychiatric sequelae of coronavirus infection have a likely multifactorial basis but are still poorly established. The direct effects of viral infection on CNS, cerebrovascular disease, physiological impairments, the inflammatory response and the immune system reaction, medical interventions, social isolation, physical discomfort, the psychological impact of a novel severe and potentially fatal illness, concerns about infecting others, and clinical/social stigma, might be all involved in the aetiological process, independently or more likely synergistically.1, 2
Interestingly, it has been recently postulated that alterations of both the dopamine and serotonin synthetic pathways might be involved in COVID-19 pathophysiology.3 The possible involvement of these neurotransmitters is suggested by a significant link – based on similarities related to gene co-expression, co-regulation and function – between Angiotensin I Converting Enzyme 2 (ACE2, encoding the main receptor to SARS-CoV-2) and Dopa Decarboxylase (DDC, encoding the enxyme that catalyzes the biosynthesis of dopamine, serotonin and histamine). In fact, evidence shows that ACE2 and DDC co-express and co-regulate in non-neuronal cell types. Furthermore, it has been demonstrated that ACE2 receptors are highly expressed in dopamine neurons and that they are reduced in Parkinson’s disease (characterized by dopamine deficiency).4 Hence, a SARS-CoV-2-induced defective expression of ACE2 might be paralleled by a DDC dysfunction, with consequent potentially altered neurotransmitters’ levels in COVID-19 patients.3
Therefore, short- and long-term neuropsychiatric disorders in COVID-19 patients could be explained – at least in part – by neurotransmission dysfunction/dysregulation.
Delirium, confusion, agitation, and sleep-wake disorders, for example, are commonly associated with alterations in melatonin (a product of serotonin), acetylcholine, dopamine, serotonin, and histamine. Furthermore, it has been demonstrated that viral infections with subsequent cytokine storm may contribute to suppressed serotonin and melatonin availability.5 Serotonin and norepinephrine are the biogenic amines most often associated with depression pathophysiology, but also dopamine play a significant role with data suggesting a reduced dopamine activity in depressed patients. Serotonin – together with norepinephrine and GABA – is one of the three major neurotransmitters associated with anxiety. Patients experiencing traumatic stress have chronically low levels of serotonin, and altered dopamine levels contributing to anhedonia, apathy, impaired attention, and motor deficits (when levels are low) and to psychotic symptoms and agitation (when levels are high).
It is obvious, however, that further experimental studies are necessary to elucidate the link between ACE2 and DDC during SARS-CoV-2 infection and to demonstrate the hypothetical alterations in dopamine, serotonin and other neurotransmitters in COVID-19 patients. More research is needed to explore the potential direct effects of COVID-19 on mental health, using both short- and long-term longitudinal investigations.
Acta Pharmacologica Sinica (2020)Cite this article
Identification of SARS-CoV-2 entry inhibitors among already approved drugs
Li Yang, Rong-juan Pei, Heng Li, Xin-na Ma, Yu Zhou, Feng-hua Zhu, Pei-lan He, Wei Tang, Ye-cheng Zhang, Jin Xiong, Shu-qi Xiao, Xian-kun Tong, Bo Zhang & Jian-ping Zuo
To discover effective drugs for COVID-19 treatment amongst already clinically approved drugs, we developed a high throughput screening assay for SARS-CoV-2 virus entry inhibitors using SARS2-S pseudotyped virus. An approved drug library of 1800 small molecular drugs was screened for SARS2 entry inhibitors and 15 active drugs were identified as specific SARS2-S pseudovirus entry inhibitors. Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that 7 of these drugs (clemastine, amiodarone, trimeprazine, bosutinib, toremifene, flupenthixol, and azelastine) significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity. Three of the drugs were classified as histamine receptor antagonists with clemastine showing the strongest anti-SARS2 activity (EC50 = 0.95 ± 0.83 µM). Our work suggests that these 7 drugs could enter into further in vivo studies and clinical investigations for COVID-19 treatment.
Predicting potential drug targets and repurposable drugs for COVID-19 via a deep generative model for graphs
Sumanta Ray1*,+, Snehalika Lall2+, Anirban Mukhopadhyay3, Sanghamitra, Bandyopadhyay2, and Alexander Schonhuth ¨1,4*
Coronavirus Disease 2019 (COVID-19) has been creating a worldwide pandemic situation. Repurposing drugs, already shown to be free of harmful side effects, for the treatment of COVID-19 patients is an important option in launching novel therapeutic strategies. Therefore, reliable molecule interaction data are a crucial basis, where drug-/protein-protein interaction networks establish invaluable, year-long carefully curated data resources. However, these resources have not yet been systematically exploited using high-performance artificial intelligence approaches. Here, we combine three networks, two of which are year-long curated, and one of which, on SARS-CoV-2-human host-virus protein interactions, was published only most recently (30th of April 2020), raising a novel network that puts drugs, human and virus proteins into mutual context. We apply Variational Graph AutoEncoders (VGAEs), representing most advanced deep learning based methodology for the analysis of data that are subject to network constraints. Reliable simulations confirm that we operate at utmost accuracy in terms of predicting missing links. We then predict hitherto unknown links between drugs and human proteins against which virus proteins preferably bind. The corresponding therapeutic agents present splendid starting points for exploring novel host-directed therapy (HDT) options.
Front Immunol. 2020; 11: 586572.
Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2
Xia Xiao, 1 , 2 , 3 , † Conghui Wang, 1 , 2 , 3 , † De Chang, 4 , † Ying Wang, 1 , 2 , 3 Xiaojing Dong, 1 , 2 , 3 Tao Jiao, 1 , 2 , 3 Zhendong Zhao, 1 Lili Ren, 1 , 2 , 3 Charles S. Dela Cruz, 5 Lokesh Sharma, 5 , * Xiaobo Lei, 1 , 2 , 3 , * and Jianwei Wang 1 , 2 , 3 , *
COVID-19 pandemic has infected millions of people with mortality exceeding >1 million. There is an urgent need to find therapeutic agents that can help clear the virus to prevent severe disease and death. Identifying effective and safer drugs can provide more options to treat COVID-19 infections either alone or in combination. Here, we performed a high throughput screening of approximately 1,700 US FDA-approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 20 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, and thioridazine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating a wide therapeutic window compared to hydroxychloroquine which had a safety index of 22 in similar experiments. Mechanistically, five of the effective compounds (fendiline HCl, monensin sodium salt, vortioxetine, sertraline HCl, and salifungin) were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA-approved compounds can provide much needed therapeutic options that we urgently need during the midst of the pandemic.
iScience. 2020 Nov 20; 23(11): 101697.
Integrative Transcriptome Analyses Empower the Anti-COVID-19 Drug Arsenal
Nehme El-Hachem,1,2,23,∗ Edward Eid,3,22 Georges Nemer,4,22 Ghassan Dbaibo,5,6,9 Ossama Abbas,3 Nelly Rubeiz,3 Salah Zeineldine,7 Ghassan M. Matar,8 Jean-Pierre Bikorimana,11 Riam Shammaa,14,15,16 Benjamin Haibe-Kains,17,18,19,20,21 Mazen Kurban,3,9,∗∗ and Moutih Rafei10,11,12,13,∗∗∗
The beginning of the 21st century has been marked by three distinct waves of zoonotic coronavirus outbreaks into the human population. The COVID-19 (coronavirus disease 2019) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emerged as a global threat endangering the livelihoods of millions worldwide. Currently, and despite collaborative efforts, diverse therapeutic strategies from ongoing clinical trials are still debated. To address the need for such an immediate call of action, we leveraged the largest dataset of drug-induced transcriptomic perturbations, public SARS-CoV-2 transcriptomic datasets, and expression profiles from normal lung transcriptomes. Most importantly, our unbiased systems biology approach prioritized more than 50 repurposable drug candidates (e.g., corticosteroids, Janus kinase and Bruton kinase inhibitors). Further clinical investigation of these FDA-approved candidates as monotherapy or in combination with an antiviral regimen (e.g., remdesivir) could lead to promising outcomes in patients with COVID-19.