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SARS-CoV-2 infection causes dopaminergic neuron senescence

Yang et al., Cell Stem Cell, doi:10.1016/j.stem.2023.12.012
Jan 2024  
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Metformin for COVID-19
3rd treatment shown to reduce risk in July 2020
*, now known with p < 0.00000000001 from 84 studies.
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3,800+ studies for 60+ treatments.
In vitro study suggesting that metformin may protect against SARS-CoV-2-induced neurological disorders. Authors show that SARS-CoV-2 infection induces senescence and inflammation in human pluripotent stem cell-derived midbrain dopamine neurons, a cell type affected in Parkinson's disease. Authors find that metformin, riluzole, and imatinib rescue cellular senescence phenotypes by inhibiting SARS-CoV-2 infection. Analyses of substantia nigra tissues (postmortem brain samples) from COVID-19 patients also detect inflammation and senescence signatures, reduced numbers of dopamine neurons and fibers, and potential Parkinson's disease pathologies.
6 preclinical studies support the efficacy of metformin for COVID-19:
A systematic review and meta-analysis of 15 non-COVID-19 preclinical studies showed that metformin inhibits pulmonary inflammation and oxidative stress, minimizes lung injury, and improves survival in animal models of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) Wang. Metformin inhibits SARS-CoV-2 in vitro Parthasarathy, Ventura-López, minimizes LPS-induced cytokine storm in a mouse model Taher, minimizes lung damage and fibrosis in a mouse model of LPS-induced ARDS Miguel, may protect against SARS-CoV-2-induced neurological disorders Yang, may be beneficial via inhibitory effects on ORF3a-mediated inflammasome activation Zhang, reduces UUO and FAN-induced kidney fibrosis Miguel, increases mitochondrial function and decreases TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells Miguel, and may improve outcomes via modulation of immune responses with increased anti-inflammatory T lymphocyte gene expression and via enhanced gut microbiota diversity Petakh.
Yang et al., 17 Jan 2024, USA, peer-reviewed, 28 authors. Contact: (corresponding author), (corresponding author),,,
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperMetforminAll
SARS-CoV-2 infection causes dopaminergic neuron senescence
Liuliu Yang, Tae Wan Kim, Yuling Han, Manoj S Nair, Oliver Harschnitz, Jiajun Zhu, Pengfei Wang, So Yeon Koo, Lauretta A Lacko, Vasuretha Chandar, Yaron Bram, Tuo Zhang, Wei Zhang, Feng He, Chendong Pan, Junjie Wu, Yaoxing Huang, Todd Evans, Paul Van Der Valk, Maarten J Titulaer, Jochem K H Spoor, Robert L Furler O’brien, Marianna Bugiani, Wilma D.J. Van De Berg, Robert E Schwartz, David D Ho, Lorenz Studer, Shuibing Chen
Cell Stem Cell, doi:10.1016/j.stem.2023.12.012
COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDAapproved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection. We also identified the inflammatory and cellular senescence signature and low levels of SARS-CoV-2 transcripts in human substantia nigra tissue of COVID-19 patients. Furthermore, we observed reduced numbers of neuromelanin+ and tyrosine-hydroxylase (TH)+ DA neurons and fibers in a cohort of severe COVID-19 patients. Our findings demonstrate that hPSC-derived DA neurons are susceptible to SARS-CoV-2, identify candidate neuroprotective drugs for COVID-19 patients, and suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.
Detailed methods are provided in the online version of this paper and include the following: DECLARATION OF INTERESTS R.E.S. is on the scientific advisory board of Miromatrix Inc. and Lime Therapeutics Inc. and is a paid consultant and speaker for Alnylam Inc. L.S. is a scientific cofounder and paid consultant of BlueRock Therapeutics Inc. and a cofounder of DaCapo Brainscience Inc. S.C. is the co-founder of OncoBeat, LLC and a paid consultant of Vesalius Therapeutics. RESOURCE AVAILABILITY Lead contact Further information and requests for resources, reagents or codes should be directed to and will be fulfilled by the lead contact, Shuibing Chen ( Materials availability This study did not generate new unique reagents. Data and code availability Single-cell RNA seq data and RNA-seq data have been deposited at GEO and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. All original code has been deposited at Github and is publicly available as of the date of publication. DOI is listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. EXPERIMENTAL MODEL AND STUDY PARTICIPANT DETAILS Human subjects A total of 31 clinically defined and pathologically confirmed brain donors were included in Cohort 2: 8 PD, 13 COVID-19, and 8 agematched control donors. During life, all donors..
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