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SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential Therapeutic Applications of Metformin

Chang et al., Biomedicines, doi:10.3390/biomedicines12061223
May 2024  
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Metformin for COVID-19
3rd treatment shown to reduce risk in July 2020, now with p < 0.00000000001 from 98 studies.
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In Vitro and rat study showing that the SARS-CoV-2 spike protein S1 subunit causes aggregation of α-synuclein and microglial activation, which may contribute to the neurological symptoms seen in long COVID. In rats, intranasal administration of S1 increased α-synuclein aggregation and microglial activation in the brain 6 weeks later. In dopaminergic neurons, S1 increased α-synuclein aggregation via both microglial inflammatory responses and direct induction of mitochondrial damage. Metformin attenuated the S1-induced inflammatory response and α-synuclein aggregation.
12 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)10. Metformin inhibits SARS-CoV-2 in vitro7,8, minimizes LPS-induced cytokine storm in a mouse model9, minimizes lung damage and fibrosis in a mouse model of LPS-induced ARDS6, may protect against SARS-CoV-2-induced neurological disorders5, may be beneficial via inhibitory effects on ORF3a-mediated inflammasome activation11, reduces UUO and FAN-induced kidney fibrosis6, increases mitochondrial function and decreases TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells6, may reduce inflammation, oxidative stress, and thrombosis via regulating glucose metabolism1, attenuates spike protein S1-induced inflammatory response and α-synuclein aggregation4, and may improve outcomes via modulation of immune responses with increased anti-inflammatory T lymphocyte gene expression and via enhanced gut microbiota diversity12.
Chang et al., 31 May 2024, peer-reviewed, 5 authors. Contact: kohyoungho122@gmail.com (corresponding author), def9207@gmail.com, ntpeace@korea.kr, lhk215@korea.kr, jiyoung0220@gmail.com.
This PaperMetforminAll
SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential Therapeutic Applications of Metformin
Moon Han Chang, Jung Hyun Park, Hye Kyung Lee, Ji Young Choi, Young Ho Koh
Biomedicines, doi:10.3390/biomedicines12061223
Abnormal aggregation of α-synuclein is the hallmark of neurodegenerative diseases, classified as α-synucleinopathies, primarily occurring sporadically. Their onset is associated with an interaction between genetic susceptibility and environmental factors such as neurotoxins, oxidative stress, inflammation, and viral infections. Recently, evidence has suggested an association between neurological complications in long COVID (sometimes referred to as 'post-acute sequelae of COVID-19') and α-synucleinopathies, but its underlying mechanisms are not completely understood. In this study, we first showed that SARS-CoV-2 Spike protein 1 (S1) induces α-synuclein aggregation associated with activation of microglial cells in the rodent model. In vitro, we demonstrated that S1 increases aggregation of α-synuclein in BE(2)M-17 dopaminergic neurons via BV-2 microglia-mediated inflammatory responses. We also identified that S1 directly affects aggregation of α-synuclein in dopaminergic neurons through increasing mitochondrial ROS, though only under conditions of sufficient α-Syn accumulation. In addition, we observed a synergistic effect between S1 and the neurotoxin MPP+ S1 treatment. Combined with a low dose of MPP+, it boosted α-synuclein aggregation and mitochondrial ROS production compared to S1 or the MPP+ treatment group. Furthermore, we evaluated the therapeutic effects of metformin. The treatment of metformin suppressed the S1-induced inflammatory response and α-synucleinopathy. Our findings demonstrate that S1 promotes α-synucleinopathy via both microglia-mediated inflammation and mitochondrial ROS, and they provide pathological insights, as well as a foundation for the clinical management of α-synucleinopathies and the onset of neurological symptoms after the COVID-19 outbreak.
Supplementary Materials: The following supporting information can be downloaded at www.mdpi.com/xxx/s1. Supplementary Figure S1 . (A) Immunoblot analysis using his-tag specific antibody to identify that S1 enter to striatum of rat brain after intranasal administration. (B) Representative images of immunoblot analysis using specific antibody for aggregated α-Syn (5G4), phospho-α-Syn (Ser129), and monomeric α-Syn in 500 ng/mL S1-treated normal BE(2)M-17. (C-E) Quantification of immunoblot analysis for aggregated α-Syn (5G4), phospho-α-Syn (Ser129), and monomeric α-Syn. (F) Representative images of TH staining in the rat substantia nigra and (G) quantification of data. All data are presented as mean ± standard error of the mean (n = 3-5 per group, * p < 0.05). Supplementary Table S1 . Lists of antibodies. Author Contributions: M.H.C.: conceptualization, writing-original draft, methodology, data curation, investigation. J.H.P.: conceptualization, writing-review and editing, methodology, data curation, investigation. H.K.L.: writing-review and editing, methodology, investigation. J.Y.C.: conceptualization, writing-review and editing. Y.H.K.: conceptualization, funding acquisition, review and supervision, writing-review and editing. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement: The animal protocol used was reviewed and approved by the KCDC-Institutional Animal Care and Use Committee (KCDC-IACUC; Approval..
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Their onset is ' 'associated with an interaction between genetic susceptibility and environmental factors such ' 'as neurotoxins, oxidative stress, inflammation, and viral infections. Recently, evidence has ' 'suggested an association between neurological complications in long COVID (sometimes referred ' 'to as ‘post-acute sequelae of COVID-19’) and α-synucleinopathies, but its underlying ' 'mechanisms are not completely understood. In this study, we first showed that SARS-CoV-2 ' 'Spike protein 1 (S1) induces α-synuclein aggregation associated with activation of microglial ' 'cells in the rodent model. In vitro, we demonstrated that S1 increases aggregation of ' 'α-synuclein in BE(2)M-17 dopaminergic neurons via BV-2 microglia-mediated inflammatory ' 'responses. We also identified that S1 directly affects aggregation of α-synuclein in ' 'dopaminergic neurons through increasing mitochondrial ROS, though only under conditions of ' 'sufficient α-Syn accumulation. In addition, we observed a synergistic effect between S1 and ' 'the neurotoxin MPP+ S1 treatment. Combined with a low dose of MPP+, it boosted α-synuclein ' 'aggregation and mitochondrial ROS production compared to S1 or the MPP+ treatment group. ' 'Furthermore, we evaluated the therapeutic effects of metformin. The treatment of metformin ' 'suppressed the S1-induced inflammatory response and α-synucleinopathy. Our findings ' 'demonstrate that S1 promotes α-synucleinopathy via both microglia-mediated inflammation and ' 'mitochondrial ROS, and they provide pathological insights, as well as a foundation for the ' 'clinical management of α-synucleinopathies and the onset of neurological symptoms after the ' 'COVID-19 outbreak.</jats:p>', 'DOI': '10.3390/biomedicines12061223', 'type': 'journal-article', 'created': {'date-parts': [[2024, 5, 31]], 'date-time': '2024-05-31T10:35:32Z', 'timestamp': 1717151732000}, 'page': '1223', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein via Microglia-Induced Inflammation ' 'and Production of Mitochondrial ROS: Potential Therapeutic Applications of Metformin', 'prefix': '10.3390', 'volume': '12', 'author': [ { 'given': 'Moon Han', 'family': 'Chang', 'sequence': 'first', 'affiliation': [ { 'name': 'Division of Brain Diseases Research, Department of Chronic ' 'Disease Convergence Research, Korea National Institute of ' 'Health, 187 Osongsaengmyeong2(i)-ro, Osong-eup, Heungdeok-gu, ' 'Cheongju-si 28159, Republic of Korea'}]}, { 'given': 'Jung Hyun', 'family': 'Park', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Brain Diseases Research, Department of Chronic ' 'Disease Convergence Research, Korea National Institute of ' 'Health, 187 Osongsaengmyeong2(i)-ro, Osong-eup, Heungdeok-gu, ' 'Cheongju-si 28159, Republic of Korea'}]}, { 'given': 'Hye Kyung', 'family': 'Lee', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Brain Diseases Research, Department of Chronic ' 'Disease Convergence Research, Korea National Institute of ' 'Health, 187 Osongsaengmyeong2(i)-ro, Osong-eup, Heungdeok-gu, ' 'Cheongju-si 28159, Republic of Korea'}]}, { 'given': 'Ji Young', 'family': 'Choi', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Brain Diseases Research, Department of Chronic ' 'Disease Convergence Research, Korea National Institute of ' 'Health, 187 Osongsaengmyeong2(i)-ro, Osong-eup, Heungdeok-gu, ' 'Cheongju-si 28159, Republic of Korea'}]}, { 'ORCID': 'http://orcid.org/0000-0001-9934-5321', 'authenticated-orcid': False, 'given': 'Young Ho', 'family': 'Koh', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Brain Diseases Research, Department of Chronic ' 'Disease Convergence Research, Korea National Institute of ' 'Health, 187 Osongsaengmyeong2(i)-ro, Osong-eup, Heungdeok-gu, ' 'Cheongju-si 28159, Republic of Korea'}]}], 'member': '1968', 'published-online': {'date-parts': [[2024, 5, 31]]}, 'reference': [ { 'key': 'ref_1', 'unstructured': 'Kovacs, G.G., and Alafuzoff, I. 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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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