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1.
Mol Med ; 28(1): 57, 2022 05 16.
Article in English | MEDLINE | ID: covidwho-1846786

ABSTRACT

BACKGROUND: Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm. METHODS: The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. RESULTS: Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. CONCLUSIONS: These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.


Subject(s)
COVID-19 , Famotidine , Animals , Anti-Inflammatory Agents , Cytokine Release Syndrome , Famotidine/pharmacology , Histamine , Histamine H2 Antagonists , Lipopolysaccharides , Mice , Reflex , Vagus Nerve , alpha7 Nicotinic Acetylcholine Receptor
5.
Int J Mol Sci ; 23(2)2022 Jan 08.
Article in English | MEDLINE | ID: covidwho-1613828

ABSTRACT

The appearance of the SARS-CoV-2 virus initiated many studies on the effects of the virus on the human body. So far, its negative influence on the functioning of many morphological and physiological units, including the nervous system, has been demonstrated. Consequently, research has been conducted on the changes that SARS-CoV-2 may cause in the cholinergic system. The aim of this study is to review the latest research from the years 2020/2021 regarding disorders in the cholinergic system caused by the SARS-CoV-2 virus. As a result of the research, it was found that the presence of the COVID-19 virus disrupts the activity of the cholinergic system, for example, causing the development of myasthenia gravis or a change in acetylcholine activity. The SARS-CoV-2 spike protein has a sequence similar to neurotoxins, capable of binding nicotinic acetylcholine receptors (nAChR). This may be proof that SARS-CoV-2 can bind nAChR. Nicotine and caffeine have similar structures to antiviral drugs, capable of binding angiotensin-converting enzyme 2 (ACE 2) epitopes that are recognized by SARS-CoV-2, with the potential to inhibit the formation of the ACE 2/SARS-CoV-2 complex. The blocking is enhanced when nicotine and caffeine are used together with antiviral drugs. This is proof that nAChR agonists can be used along with antiviral drugs in COVID-19 therapy. As a result, it is possible to develop COVID-19 therapies that use these compounds to reduce cytokine production. Another promising therapy is non-invasive stimulation of the vagus nerve, which soothes the body's cytokine storm. Research on the influence of COVID-19 on the cholinergic system is an area that should continue to be developed as there is a need for further research. It can be firmly stated that COVID-19 causes a dysregulation of the cholinergic system, which leads to a need for further research, because there are many promising therapies that will prevent the SARS-CoV-2 virus from binding to the nicotinic receptor. There is a need for further research, both in vitro and in vivo. It should be noted that in the functioning of the cholinergic system and its connection with the activity of the COVID-19 virus, there might be many promising dependencies and solutions.


Subject(s)
COVID-19/complications , COVID-19/virology , Cholinergic Neurons/virology , Acetylcholinesterase/metabolism , Animals , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/virology , Humans , Myasthenia Gravis/virology , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/virology , Vagus Nerve/drug effects , Vagus Nerve/virology
7.
PLoS One ; 16(10): e0258841, 2021.
Article in English | MEDLINE | ID: covidwho-1496516

ABSTRACT

BACKGROUND: Patients with COVID-19 present with a variety of clinical manifestations, ranging from mild or asymptomatic disease to severe illness and death. Whilst previous studies have clarified these and several other aspects of COVID-19, one of the ongoing challenges regarding COVID-19 is to determine which patients are at risk of adverse outcomes of COVID-19 infection. It is hypothesized that this is the result of insufficient inhibition of the immune response, with the vagus nerve being an important neuro-immuno-modulator of inflammation. Vagus nerve activity can be non-invasively indexed by heart-rate-variability (HRV). Therefore, we aimed to assess the prognostic value of HRV, as a surrogate marker for vagus nerve activity, in predicting mortality and intensive care unit (ICU) referral, in patients hospitalized with COVID-19. METHODS: A retrospective cohort study including all consecutive patients (n = 271) diagnosed and hospitalized with COVID-19 between March 2020 and May 2020, without a history of cardiac arrhythmias (including atrial and ventricular premature contractions), pacemaker, or current bradycardia (heart rate <50 bpm) or tachycardia (heart rate >110 bpm). HRV was based on one 10s ECG recorded at admission. 3-week survival and ICU referral were examined. RESULTS: HRV indexed as standard deviation of normal to normal heartbeat intervals (SDNN) predicted survival (H.R. = 0.53 95%CI: 0.31-0.92). This protective role was observed only in patients aged 70 years and older, not in younger patients. HRV below median value also predicted ICU referral within the first week of hospitalization (H.R = 0.51, 95%CI: 0.29-0.90, P = 0.021). CONCLUSION: Higher HRV predicts greater chances of survival, especially in patients aged 70 years and older with COVID-19, independent of major prognostic factors. Low HRV predicts ICU indication and admission in the first week after hospitalization.


Subject(s)
COVID-19/mortality , Heart Rate/physiology , Age Factors , Aged , Aged, 80 and over , COVID-19/metabolism , Electrocardiography, Ambulatory , Female , Heart/physiopathology , Heart Atria/physiopathology , Humans , Male , Middle Aged , Myocardium/metabolism , Prognosis , Retrospective Studies , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Treatment Outcome , Vagus Nerve/physiopathology
8.
Front Immunol ; 11: 595342, 2020.
Article in English | MEDLINE | ID: covidwho-1106024

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) underlined the urgent need for alleviating cytokine storm. We propose here that activating the cholinergic anti-inflammatory pathway (CAP) is a potential therapeutic strategy. However, there is currently no approved drugs targeting the regulatory pathway. It is evident that nicotine, anisodamine and some herb medicine, activate the CAP and exert anti-inflammation action in vitro and in vivo. As the vagus nerve affects both inflammation and specific immune response, we propose that vagus nerve stimulation by invasive or non-invasive devices and acupuncture at ST36, PC6, or GV20, are also feasible approaches to activate the CAP and control COVID-19. It is worth to investigate the efficacy and safety of the strategy in patients with COVID-19.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/therapy , Neuroimmunomodulation/immunology , Vagus Nerve Stimulation/methods , Vagus Nerve/immunology , Acupuncture , Anti-Inflammatory Agents/pharmacology , Cytokines/blood , Drugs, Chinese Herbal/pharmacology , Humans , Inflammation/therapy , Nicotine/pharmacology , SARS-CoV-2 , Solanaceous Alkaloids/pharmacology
9.
Neurosci Biobehav Rev ; 125: 1-10, 2021 06.
Article in English | MEDLINE | ID: covidwho-1078104

ABSTRACT

The COVID-19 pandemic has led to widespread increases in mental health problems, including anxiety and depression. The development of these and other psychiatric disorders may be related to changes in immune, endocrine, autonomic, cognitive, and affective processes induced by a SARS-CoV-2 infection. Interestingly, many of these same changes can be triggered by psychosocial stressors such as social isolation and rejection, which have become increasingly common due to public policies aimed at reducing the spread of SARS-CoV-2. The present review aims to shed light on these issues by describing how viral infections and stress affect mental health. First, we describe the multi-level mechanisms linking viral infection and life stress exposure with risk for psychopathology. Then, we summarize how resilience can be enhanced by targeting vagus nerve function by, for example, applying transcutaneous vagus nerve stimulation and targeting lifestyle factors, such as exercise. With these biopsychosocial insights in mind, researchers and healthcare professionals will be better equipped to reduce risk for psychopathology and increase resilience during this challenging pandemic period and beyond.


Subject(s)
COVID-19 , Pandemics , Anxiety , Depression , Humans , Mental Health , SARS-CoV-2 , Vagus Nerve
10.
Pharmacol Ther ; 222: 107794, 2021 06.
Article in English | MEDLINE | ID: covidwho-968657

ABSTRACT

Obesity and the metabolic syndrome (MetS), which have reached pandemic proportions significantly increase the risk for type 2 diabetes, cardiovascular disease, and other serious conditions. Recent data with COVID-19 patients indicate that obesity also is a significant risk factor for this novel viral disease and poor outcome of associated critical illness. These findings considerably change the view of obesity as a driver of serious, but slowly-progressing chronic diseases, and emphasize the urgency to explore new therapeutic approaches. Inflammation is a recognized driver of metabolic derangements in obesity and MetS, and a core feature of COVID-19 pathobiology. Recent advances in our understanding of inflammatory regulation have highlighted the role of the nervous system and the vagus nerve-based inflammatory reflex. Current bioelectronic and pharmacological therapeutic explorations centered on the inflammatory reflex offer new approaches for conditions characterized by immune and metabolic dysregulation and for ameliorating the escalating burden of obesity, MetS, and COVID-19.


Subject(s)
COVID-19 , Inflammation , Obesity , Vagus Nerve/immunology , COVID-19/immunology , COVID-19/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Metabolic Syndrome/immunology , Obesity/epidemiology , Obesity/immunology , Obesity/therapy , SARS-CoV-2
14.
Neurol Sci ; 41(10): 2657-2669, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-680556

ABSTRACT

Respiratory viruses are opportunistic pathogens that infect the upper respiratory tract in humans and cause severe illnesses, especially in vulnerable populations. Some viruses have neuroinvasive properties and activate the immune response in the brain. These immune events may be neuroprotective or they may cause long-term damage similar to what is seen in some neurodegenerative diseases. The new "Severe Acute Respiratory Syndrome Coronavirus 2" (SARS-CoV-2) is one of the Respiratory viruses causing highly acute lethal pneumonia coronavirus disease 2019 (COVID-19) with clinical similarities to those reported in "Severe Acute Respiratory Syndrome Coronavirus"(SARS-CoV) and the "Middle East Respiratory Syndrome Coronavirus"(MERS-CoV) including neurological manifestation. To examine the possible neurological damage induced by SARS-CoV-2, it is necessary to understand the immune reactions to viral infection in the brain, and their short- and long-term consequences. Considering the similarities between SARS-CoV and SARS-CoV-2, which will be discussed, cooperative homological and phylogenetical studies lead us to question if SARS-CoV-2 can have similar neuroinvasive capacities and neuroinflammatiory events that may lead to the same short- and long-term neuropathologies that SARS-CoV had shown in human and animal models. To explain the neurological manifestation caused by SARS-CoV-2, we will present a literature review of 765 COVID-19 patients, in which 18% had neurological symptoms and complications, including encephalopathy, encephalitis and cerebrovascular pathologies, acute myelitis, and Guillain-Barré syndrome. Clinical studies describe anosmia or partial loss of the sense of smell as the most frequent symptom in COVID19 patients, suggesting that olfactory dysfunction and the initial ultrarapid immune responses could be a prognostic factor.


Subject(s)
Betacoronavirus , Brain/virology , Coronavirus Infections/complications , Nervous System Diseases/etiology , Nervous System Diseases/virology , Pneumonia, Viral/complications , Vagus Nerve/virology , Blood-Brain Barrier/pathology , Blood-Brain Barrier/virology , Brain/pathology , COVID-19 , Coronavirus Infections/pathology , Humans , Nervous System Diseases/pathology , Pandemics , Pneumonia, Viral/pathology , SARS-CoV-2 , Vagus Nerve/pathology
15.
Med Hypotheses ; 143: 110093, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-650684

ABSTRACT

The COVID-19 pandemic has rapidly spread all over the world and caused a major health care crisis. About 20% of patients develop severe disease and require hospitalisation, which is associated with a high mortality rate of up to 97% in those being ventilated and respiratory failure being the leading cause of death. Despite many therapeutic agents being under current investigation there is yet no panacea available. With increasing rates of infection throughout the world, there is an urgent need for new therapeutic approaches to counteract the infection. As the nervous system has shown to be a strong modulator of respiratory function and the immune response, we want to highlight pathways involved in regulation of respiratory function, the neuro-immune axis as well as the rationale for a potential targeted treatment of fulminant acute respiratory distress syndrome via transcutaneous non-invasive vagal nerve stimulation in critically-ill COVID-19 patients.


Subject(s)
Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Respiratory Distress Syndrome/therapy , Vagus Nerve Stimulation/methods , Autonomic Nervous System , Betacoronavirus , COVID-19 , Critical Illness , Humans , Immune System , Pandemics , Respiration, Artificial , SARS-CoV-2 , Vagus Nerve/physiology
16.
ACS Chem Neurosci ; 11(14): 2048-2050, 2020 07 15.
Article in English | MEDLINE | ID: covidwho-627315

ABSTRACT

In COVID-19, lung manifestations present as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and microvascular thrombosis. Currently, these manifestations are considered to be only consequences of pulmonary SARS-CoV-2 virus infection. We are proposing a new hypothesis that neurogenic insult may also play a major role in the pathogenesis of these manifestations. SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius (NTS) may play a role in the acute exacerbation of pulmonary edema and microvascular clotting in COVID-19 patients.


Subject(s)
Coronavirus Infections/physiopathology , Hypotension/physiopathology , Lung/blood supply , Microvessels/physiopathology , Pneumonia, Viral/physiopathology , Pulmonary Edema/physiopathology , Solitary Nucleus/physiopathology , Thrombosis/physiopathology , Betacoronavirus , COVID-19 , Capillary Permeability/physiology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/physiopathology , Facial Nerve , Glossopharyngeal Nerve , Humans , Inflammation , Lung/immunology , Microvessels/immunology , Pandemics , Parasympathetic Nervous System/physiopathology , Pneumonia, Viral/immunology , Pulmonary Edema/immunology , SARS-CoV-2 , Solitary Nucleus/immunology , Vagus Nerve , Vasoconstriction
18.
ACS Chem Neurosci ; 11(11): 1520-1522, 2020 06 03.
Article in English | MEDLINE | ID: covidwho-324525

ABSTRACT

Accumulating data have now shown strong evidence that COVID-19 infection leads to the occurrence of neurological signs with different injury severity. Anosmia and agueusia are now well documented and included in the criteria list for diagnosis, and specialists have stressed that doctors screen COVID-19 patients for these two signs. The eventual brainstem dysregulation, due to the invasion of SARS CoV-2, as a cause of respiratory problems linked to COVID-19, has also been extensively discussed. All these findings lead to an implication of the central nervous system in the pathophysiology of COVID-19. Here we provide additional elements that could explain other described signs like appetite loss, vomiting, and nausea. For this, we investigated the role of brainstem structures located in the medulla oblongata involved in food intake and vomiting control. We also discussed the possible pathways the virus uses to reach the brainstem, i.e., neurotropic and hematogenous (with its two variants) routes.


Subject(s)
Anorexia/physiopathology , Appetite Regulation/physiology , Autonomic Nervous System/physiopathology , Coronavirus Infections/physiopathology , Eating/physiology , Nausea/physiopathology , Pneumonia, Viral/physiopathology , Solitary Nucleus/physiopathology , Vomiting/physiopathology , Ageusia/etiology , Anorexia/etiology , Area Postrema/physiopathology , Blood-Brain Barrier , COVID-19 , Coronavirus Infections/complications , Humans , Hypothalamus/physiopathology , Medulla Oblongata/physiopathology , Nausea/etiology , Neural Pathways/physiopathology , Olfaction Disorders/etiology , Olfactory Nerve , Pandemics , Pneumonia, Viral/complications , Vagus Nerve , Vomiting/etiology
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