Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: The possible role of the sigma-1 receptor and autophagy

Mendelson

et al. 2021

Preprint

Background: The SARS-CoV2 virus continues to have devastating consequences worldwide. Though vaccinations have helped to reduce the impact of the virus, new strains still pose a threat to unvaccinated, and to a lesser extent vaccinated, individuals. Therefore, it is imperative to identify treatments that can prevent the development of severe COVID-19. Recently, acute use of SSRI antidepressants in COVID+ patients has been shown to reduce the severity of symptoms compared to placebo. Since SSRIs are a widely used anti-depressant, the aim of this study was to determine if COVID+ patients already on SSRI treatment upon admission to the hospital had reduced mortality compared to COVID+ patients not on chronic SSRI treatment. Methods: A retrospective observational study design was used. Electronic medical records of 9,043 patients with a laboratory-confirmed diagnosis of Covid-19 from 03/2020 to 03/2021from six hospitals were queried for demographic and clinical information. Using R, a logistic regression model was run with mortality as the outcome and SSRI status as the exposure. An adjusted logistic regression model was run to account for age category, gender, and race. All tests were considered significant at p of 0.05 or less. Results: In this sample, no patients admitted on SSRIs had them discontinued. This is consistent with current recommendations. There was no significant difference in the odds of dying between COVID+ patients on chronic SSRIs vs COVID+ patients not taking SSRIs, after controlling for age category, gender, and race. The odds of COVID+ patients on SSRIs dying was 0.98 (95%CI: 0.81, 1.18) compared to COVID+ patients not on SSRIs (p=0.83). Conclusion: In times of pandemics due to novel infectious agents it is difficult, but critical to evaluate safety and efficacy of drugs that might be repurposed for treatment. This large sample size of 9,043 patients suggests that there will be no significant benefit to use of SSRIs to decrease mortality rates for hospitalized patients with Covid-19 who are not currently on SSRI medications. This study shows the utility of large clinical databases in addressing the urgent issue of determining what commonly prescribed drugs might be useful in treating COVID-19.

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 89%

Ongoing use of SSRIs and the hospital course of COVID-19 patients: a retrospective outcome analysis

Mendelson

et al. 2021

Preprint

“…Hence, targeting Sig-1R may regulate ER stress, a common mechanism displayed in neurodegeneration [ 107 ]. Interestingly, Sig-1R ligands have been found to potentially offer protection against the most severe symptoms of SARS-CoV-2, providing mitochondrial protection, activating mitophagy, preventing ER-stress, managing Ca 2+ transport, and inducing autophagy to prevent cell death in response to infection [ 108 ].…”

Section: Therapeutic Approaches Targeting Mamsmentioning

confidence: 99%

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

et al. 2022

Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

“…Macroautophagy, otherwise known as autophagy, is a conserved catabolic mechanism, which degrades excess, unrequired, or damaged cellular components. Autophagy is under the control of several pathways and thus a target for multiple disease states, including bacterial infection [ 23 ], viral infection [ 24 ], neurodegenerative diseases [ 25 ], cancer [ 26 ], and diabetes [ 27 ]. Autophagy has been studied extensively in yeast ( Saccharomyces cerevisiae ) as a mechanism to stand starvation conditions [ 28 ], where the yeast cells would consume their cellular components, attempting to survive starvation, and this is the origin of the term autophagy (literally meaning self-eating).…”

Section: Introductionmentioning

confidence: 99%

Plant Polyphenols for Aging Health: Implication from Their Autophagy Modulating Properties in Age-Associated Diseases

et al. 2021

Self Cite

Polyphenols are a family of naturally occurring organic compounds, majorly present in fruits, vegetables, and cereals, characterised by multiple phenol units, including flavonoids, tannic acid, and ellagitannin. Some well-known polyphenols include resveratrol, quercetin, curcumin, epigallocatechin gallate, catechin, hesperetin, cyanidin, procyanidin, caffeic acid, and genistein. They can modulate different pathways inside the host, thereby inducing various health benefits. Autophagy is a conserved process that maintains cellular homeostasis by clearing the damaged cellular components and balancing cellular survival and overall health. Polyphenols could maintain autophagic equilibrium, thereby providing various health benefits in mediating neuroprotection and exhibiting anticancer and antidiabetic properties. They could limit brain damage by dismantling misfolded proteins and dysfunctional mitochondria, thereby activating autophagy and eliciting neuroprotection. An anticarcinogenic mechanism is stimulated by modulating canonical and non-canonical signalling pathways. Polyphenols could also decrease insulin resistance and inhibit loss of pancreatic islet β-cell mass and function from inducing antidiabetic activity. Polyphenols are usually included in the diet and may not cause significant side effects that could be effectively used to prevent and treat major diseases and ailments.