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  3. Pharmacological inhibition of CK2 by silmitasertib mitigates sepsis-induced circulatory collapse, thus improving septic outcomes in mice

Pharmacological inhibition of CK2 by silmitasertib mitigates sepsis-induced circulatory collapse, thus improving septic outcomes in mice

  • Biomed Pharmacother. 2024 Sep:178:117191. doi: 10.1016/j.biopha.2024.117191.
Gustavo Ferreira Alves 1,  Eleonora Aimaretti 2,  Maria Luísa da Silveira Hahmeyer 3,  Giacomo Einaudi 4,  Elisa Porchietto 4,  Chiara Rubeo 2,  Enrica Marzani 5,  Manuela Aragno 2,  José Eduardo da Silva-Santos 3,  Carlo Cifani 4,  Daniel Fernandes 3,  Massimo Collino 6
Affiliations

Affiliations

  • 1 Department of Neurosciences (Rita Levi Montalcini), University of Turin, Turin, Italy; Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Brazil; Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy.
  • 2 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
  • 3 Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Brazil.
  • 4 Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy.
  • 5 Department of Neurosciences (Rita Levi Montalcini), University of Turin, Turin, Italy.
  • 6 Department of Neurosciences (Rita Levi Montalcini), University of Turin, Turin, Italy. Electronic address: massimo.collino@unito.it.
PMID: 39079263 DOI: 10.1016/j.biopha.2024.117191
Abstract

Casein Kinase II (CK2) has recently emerged as a pivotal mediator in the propagation of inflammation across various diseases. Nevertheless, its role in the pathogenesis of sepsis remains unexplored. Here, we investigated the involvement of CK2 in sepsis progression and the potential beneficial effects of silmitasertib, a selective and potent CK2α inhibitor, currently under clinical trials for COVID-19 and Cancer. Sepsis was induced by caecal ligation and puncture (CLP) in four-month-old C57BL/6OlaHsd mice. One hour after the CLP/Sham procedure, Animals were assigned to receive silmitasertib (50 mg/kg/i.v.) or vehicle. Plasma/organs were collected at 24 h for analysis. A second set of experiments was performed for survival rate over 120 h. Septic mice developed multiorgan failure, including renal dysfunction due to hypoperfusion (reduced renal blood flow) and increased plasma levels of creatinine. Renal derangements were associated with local overactivation of CK2, and downstream activation of the NF-ĸB-iNOS-NO axis, paralleled by a systemic cytokine storm. Interestingly, all markers of injury/inflammation were mitigated following silmitasertib administration. Additionally, when compared to sham-operated mice, sepsis led to vascular hyporesponsiveness due to an aberrant systemic and local release of NO. Silmitasertib restored sepsis-induced vascular abnormalities. Overall, these pharmacological effects of silmitasertib significantly reduced sepsis mortality. Our findings reveal, for the first time, the potential benefits of a selective and potent CK2 Inhibitor to counteract sepsis-induced hyperinflammatory storm, vasoplegia, and ultimately prolonging the survival of septic mice, thus suggesting a pivotal role of CK2 in sepsis and silmitasertib as a novel powerful pharmacological tool for drug repurposing in sepsis.

Keywords

CX-4945; Casein Kinase-2; Inflammation; Nitric oxide; Septic shock; Vasoplegia.

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