Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a “Systemic AhR Activation Syndrome” (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.

No abstract

Glutamate (Glu) and γ-aminobutyric acid (GABA) are major neurotransmitters in the mammalian brain which regulate brain development at molecular, cellular, and systems level. Sedative, anesthetic, and antiepileptic drugs (AEDs) interact with glutamate and GABA receptors to produce their desired effects. The question is posed whether such interference with glutamatergic and GABAergic neurotransmission may exert undesired, and perhaps even detrimental effects on human brain development. Preclinical research in rodents and non-human primates has provided extensive evidence that sedative, anesthetic, and AEDs can trigger suicide of neurons and oligodendroglia, suppress neurogenesis, and inhibit normal synapse development and sculpting. Behavioral correlates in rodents and non-human primates consist of long-lasting cognitive impairment. Retrospective clinical studies in humans exposed to anesthetics or AEDs in utero, during infancy or early childhood have delivered conflicting but concerning results in terms of a correlation between drug exposure and impaired neurodevelopmental outcomes. Prospective studies are currently ongoing. This review provides a short overview of the current state of knowledge on this topic.

Background High definition transcranial direct current stimulation (HD-tDCS) has been administered over single brain regions for small numbers of sessions. Safety, feasibility and tolerability of HD-tDCS over multiple brain regions, multiple daily stimulations and long periods are not established. Objective We studied safety, feasibility and tolerability of daily HD-tDCS over 2–4 brain regions for 20 sessions in healthy adults. Methods Five healthy adults underwent physical and neurological examination, electrocardiogram (EKG), electroencephalogram (EEG) and cognitive screening (ImpACT) before, during and after HD-tDCS. Four networks (left/right temporoparietal and frontal) were stimulated in sequence (20 min each) using HD-tDCS in 20 daily sessions. Sessions 1–10 included sequential stimulation of both temporoparietal networks, sessions 11–15 stimulations of 4 networks and sessions 16–20 two daily stimulation cycles of 4 networks/cycle (1.5 mA/network). Side effects, ImpACT scores and EEG power spectrum were compared before and after HD-tDCS. Results All subjects completed the trial. Adverse events were tingling, transient redness at the stimulation site, perception of continuing stimulation after end of session and one self-resolving headache. EEG power spectrum showed decreased delta power in frontal areas several days after HD-tDCS. While at the group level ImpACT scores did not differ before and after stimulations, we found a trend for correlation between decreased EEG delta power and individual improvements in ImpACT scores after HD-tDCS. Conclusion Prolonged, repeat daily stimulation of multiple brain regions using HD-tDCS is feasible and safe in healthy adults. Preliminary EEG results suggest that HD-tDCS may induce long lasting changes in excitability in the brain.