“In conclusion, at present it is unclear whether a Sig-1R agonist or Sig-1R antagonist would be better for inhibiting SARS-CoV-2 replication. Experiments comparing these ligands in the same assay are warranted. Until then, classifying anti- inflammatory anaesthesia drugs such as dexmedetomidine21 as ‘pro-viral’ based on their agonistic activity on Sig-1R is not supported by evidence.”
Jain A, Lamperti M, Doyle DJ, Lobo FA. Anaesthesia drugs, SARS-CoV-2, and the sigma-1 receptor: a complex affair. Comment on Br J Anaesth 2021; 127: e32-4. Br J Anaesth. 2021 Sep 20:S0007-0912(21)00579-1. doi: 10.1016/j.bja.2021.09.008. Epub ahead of print. PMID: 34635287; PMCID: PMC8500736.
“Asymptomatic infections have been widely reported for COVID-19. However, many studies do not distinguish between the presymptomatic stage and truly asymptomatic infections. We conducted a systematic review and meta-analysis of COVID-19 literature reporting laboratory-confirmed infections to determine the burden of asymptomatic infections and removed index cases from our calculations to avoid conflation. By analyzing over 350 papers, we estimated that more than one-third of infections are truly asymptomatic. We found evidence of greater asymptomaticity in children compared with the elderly, and lower asymptomaticity among cases with comorbidities compared to cases with no underlying medical conditions. Greater asymptomaticity at younger ages suggests that heightened vigilance is needed among these individuals, to prevent spillover into the broader community.”
Abstract: “Blood-brain barrier (BBB) disruption is one of the most important pathological manifestations of ischemic stroke. Reducing BBB collapse is effective in alleviating brain parenchymal injury and cognitive dysfunction. Our previous study reported that Sigma-1 receptor (Sig-1R) activation in cerebral microvascular endothelial cells (CMECs) ameliorated BBB impairment, but the detailed mechanism remains unclear. In this study, we investigated Sig-1R activation as a BBB integrity promoter via many post ischemic stroke pathways. Sig-1R activation in BBB-associated astrocytes can increase glia-derived neurotrophic factor (GDNF) secretion in bilateral common carotid artery occlusion (BCCAO) mice. Upregulated GDNF activates its receptors in CMECs to promote BBB integrity, and activated Sig-1R in CMECs facilitates this process. In vitro experiments have found that Sig-1R activation in CMECs promotes the interaction between the GDNF α1 receptor and transduction rearrangement gene, increasing PI3K-AKT-junction protein signaling pathway expression. Sig-1R activation could be an effective therapeutic method for preventing BBB damage in ischemic stroke and other neurological conditions.”
Liu D, Yang L, Liu P, Ji X, Qi X, Wang Z, Chi T, Zou L. Sigma-1 receptor activation alleviates blood-brain barrier disruption post cerebral ischemia stroke by stimulating the GDNF-GFRα1-RET pathway. Exp Neurol. 2021 Sep 25:113867. doi: 10.1016/j.expneurol.2021.113867. Epub ahead of print. PMID: 34582837.
“The prefrontal cortex of the human brain is larger than that of other species. Comparisons of mouse, macaque and human brains uncover some of the genetic and molecular factors behind these differences….”
Wallace JL and Pollen AA: The genetic symphony underlying evolution of the brain’s prefrontal cortex. Nature (News and Views, October 1, 2021), doi: https://doi.org/10.1038/d41586-021-02460-3
“Defenses against SARS-CoV-2 variants
Our key defense against the COVID-19 pandemic is neutralizing antibodies against the SARS-CoV-2 virus elicited by natural infection or vaccination. Recent emerging viral variants have raised concern because of their potential to escape antibody neutralization. Wang et al. identified four antibodies from early-outbreak convalescent donors that are potent against 23 variants, including variants of concern, and characterized their binding to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Yuan et al. examined the impact of emerging mutations in the receptor-binding domain of the spike protein on binding to the host receptor ACE2 and to a range of antibodies. These studies may be helpful for developing more broadly effective vaccines and therapeutic antibodies. “
Wang L, Zhou T., Zhang Y., Yang ES, …Misasi J: Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants. Science (13 Aug 2021) Vol 373, Issue 6556 DOI: 10.1126/science.abh1766
Abstract: “Adult neurogenesis in the hippocampal dentate gyrus (DG) is an extraordinary form of plasticity fundamental for cognitive flexibility. Recent evidence showed that newborn neurons differentially modulate input to the infra- and supra-pyramidal blades of the DG during the processing of spatial and contextual information, respectively. However, how this differential regulation by neurogenesis is translated into different aspects contributing cognitive flexibility is unclear. Here, we increased adult-born neurons by a genetic expansion of neural stem cells and studied their influence during navigational learning. We found that increased neurogenesis improved both memory precision and flexibility. Interestingly, each of these gains was associated with distinct subregional patterns of activity and better separation of memory representations in the DG-CA3 network. Our results highlight the role of adult-born neurons in promoting memory precision and indexing and suggests their anatomical allocation within specific DG-CA3 compartments, together contributing to cognitive flexibility.”
Berdugo-Vega G, Lee CC, Garthe A, Kempermann G, Calegari F. Adult-born neurons promote cognitive flexibility by improving memory precision and indexing. Hippocampus. 2021 Oct;31(10):1068-1079. doi: 10.1002/hipo.23373. Epub 2021 Jun 26. PMID: 34174010.
”The novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The escalating number of SARS-CoV-2-infected individuals has conferred the viral spread with the status of global pandemic. However, there are no prophylactic or therapeutic drugs available on the market to treat COVID-19, although several drugs have been approved. Recently, two articles using the comparative viral-human protein–protein interaction map revealed that the sigma-1 receptor in the endoplasmic reticulum plays an important role in SARS-CoV-2 replication in cells. Knockout and knockdown of SIGMAR1 (sigma-1 receptor, encoded by SIGMAR1) caused robust reductions in SARS-CoV-2 replication, which indicates that the sigma-1 receptor is a key therapeutic target for SARS-CoV-2 replication. Interestingly, a recent clinical trial demonstrated that treatment with the antidepressant fluvoxamine, which has a high affinity at the sigma-1 receptor, could prevent clinical deterioration in adult outpatients infected with SARS-CoV-2. In this review, we discuss the brief history of the sigma-1 receptor and its role in SARS-CoV-2 replication in cells. Here, we propose repurposing of traditional central nervous system (CNS) drugs that have a high affinity at the sigma-1 receptor (i.e., fluvoxamine, donepezil, ifenprodil) for the treatment of SARS-CoV-2-infected patients. Finally, we discussed the potential of other CNS candidates such as cutamesine and arketamine.”
Hashimoto, K. Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor. Eur Arch Psychiatry Clin Neurosci 271, 249–258 (2021). https://doi.org/10.1007/s00406-020-01231-x
Abstract: “The gut-brain axis is a bidirectional communication system which allows the central nervous system and gastrointestinal tract to interact with and respond to each other rapidly and effectively. It is becoming increasingly clear that major players in this complex system are gut bacteria. The mechanisms of signal transmission from bacteria to the brain are complex and not fully elucidated, but include neural, endocrine, immune, and metabolic pathways. It was initially demonstrated in a rodent model of depression that the gut microbiota was altered. This observation has been replicated in patients with major depression who show decreased microbial diversity. Furthermore, when rodents receive a microbiota transplant from a depressed patient their behaviour alters, as does their tryptophan metabolism and immune status. Several studies of psychobiotics (bacteria with a potential mental health benefit) have been conducted in healthy populations and in patients with depression. While some psychobiotics have shown efficacy in treating depression, other bacteria have yielded negative findings. Larger-scale, well-designed studies are required. EU-funded guidelines recommend that patients with depression or vulnerability to depression should be encouraged to enhance a plant-based diet with a high content of grains/fibres, fermented foods, and fish. A significant impact of such a diet is likely mediated through the gut microbiota.”
Dinan TG et al., Psychobiotics:Evolution of Novel Antidepressants. Mod. Trends Psychiatry 32: 134-143 (2021). doi: 10.1159/000510424.
Abstract: “Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene–environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic ‘priming’ of offspring microglia and postnatal immune–brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.”
Han, V.X., Patel, S., Jones, H.F. et al. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nature Reviews Neurol. 17: 564–579 (2021). https://doi.org/10.1038/s41582-021-00530-8