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Anti‑inflammatory effect of metformin against an experimental model of LPS‑induced cytokine storm

Taher et al., Experimental and Therapeutic Medicine, doi:10.3892/etm.2023.12114
Jul 2023  
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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.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
Mouse study showing that metformin attenuated LPS-induced increases in inflammatory cytokines, demonstrating an anti-inflammatory effect that may be useful against cytokine storm.
60 female mice were pretreated with oral or intraperitoneal (IP) metformin daily for 30 days. Lipopolysaccharide (LPS) was then injected to induce a cytokine storm and trigger inflammation. Metformin pretreatment, both oral and IP, significantly reduced the LPS-induced increase in serum levels of the proinflammatory cytokines IL-1β, IL-6, and TNF-α. IP metformin was more effective than oral metformin at reducing IL-6 levels. Neither oral nor IP metformin had a significant effect on IL-17 levels.
The results suggest metformin may have potential to suppress damaging inflammatory cytokine storms, suggesting benefit for treating cytokine storm-related diseases like COVID-19.
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.
Taher et al., 13 Jul 2023, peer-reviewed, 4 authors. Contact:
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Anti‑inflammatory effect of metformin against an experimental model of LPS‑induced cytokine storm
Dr Ibrahim Taher, Eman El‑masry, Mohamed Abouelkheir, Ahmed E Taha
Experimental and Therapeutic Medicine, doi:10.3892/etm.2023.12114
Cytokine storm is one of the leading causes of death in patients with COVID-19. Metformin has been shown to inhibit the action of a wide range of proinflammatory cytokines such as IL-6, and TNF-α which may ultimately affect cytokine storm due to Covid-19. The present study analyzed the anti-inflammatory effect of oral and intraperitoneal (IP) metformin administration routes in a mouse model of lipopolysaccharide (LPS)-induced cytokine storm. A total of 60 female BALB/c mice were randomly assigned to one of six groups: i) Control; ii) LPS model; iii) oral saline + LPS; iv) oral metformin + LPS; v) IP saline + LPS; and vi) IP metformin + LPS. Metformin or saline were administered to the mice for 30 days, after which an IP injection of 0.5 mg/kg LPS induced a cytokine storm in the five treatment groups. Mice were sacrificed and serum cytokine levels were measured. Pretreatment of mice with either oral or IP metformin significantly reduced the increase in IL-1, IL-6 and TNF-α following LPS injection. Both metformin administration routes significantly reduced IL-1 and TNF-α levels, although IP metformin appeared to be significantly more effective at reducing IL-6 levels compared with oral metformin. Neither the oral or IP route of administration of metformin demonstrated a significant effect on IL-17 levels. Based on its ability to suppress the proinflammatory LPS-induced cytokine storm, metformin may have future potential benefits in ameliorating human diseases caused by elevated cytokine levels.
Authors' contributions All of the authors have made substantial contributions towards the completion of the present study. MA and AET conceived the present study, performed the experiments, were project administrators and prepared the draft manuscript. IAT, EAEM, MA and AET collected the data, obtained resources, performed data analysis and critically reviewed and edited the manuscript. IAT and EAEM acquired funding. IAT, MA and AET supervised the project. IAT and AET confirm the authenticity of the raw data. All authors read and approved the final version of the manuscript. Ethics approval and consent to participate Ethical approval was obtained from the Local Committee of Bioethics of Jouf University (approval no. 07-08-42; Sakaka, Saudi Arabia). Patient consent for publication Not applicable. Competing interests The authors declare that they have no competing interests.
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