Protective Effects of cyclosporine and NIM-811 in murine hepatic ischemia-reperfusion injury model

During hepatic surgery or liver transplantation, the liver is vulnerable to ischemia-reperfusion injury (IRI), especially when vessels are compressed to control bleeding or during periods of ischemia. The hallmark of IRI comprises mitochondrial dysfunction, which generates reactive oxygen species, and cell death through necrosis or apoptosis. Cyclosporine (CsA), a well-known immunosuppressive agent that inhibits calcineurin, has the additional effect of inhibiting the mitochondrial permeability transition pore (mPTP), and hence preventing mitochondrial swelling and injury. NIM-811, which is the nonimmunosuppressive analog of CsA, has a similar effect on mPTP.

In this research, NIM-811 served as an important control to identify a comparable effect with CsA, without the immunosuppressive action. Compared with the control mice, the mice treated with 10 and 25 mg/kg of CsA and NIM-811 had significantly lower serum alanine transaminase (ALT) levels. Moreover, the liver tissue showed reduced histological injury scores after treatment with CsA at 2.5, 10, and 25 mg/kg and NIM-811 and significant decrease in apoptosis after treatment with CsA at all doses.

Furthermore, the levels of the pro-inflammatory cytokines, particularly interleukin (IL)-1β, IL-2, IL-4, IL-10, and keratinocyte chemoattractant/human growth-regulated oncogene significantly decreased in the mice treated with the highest dose of CsA (25 mg/kg) than those in the control mice. 

The study was published in the KeAi journal Liver Research.

The findings provide evidence that CsA can reduce hepatic warm IRI in a murine model. Similar findings with the use of its nonimmunosuppressive analog NIM-811 suggested that the protection was unlikely mediated by immunosuppressive pathways. Furthermore, these results have potential implications on mitigating IRI during liver transplantation and resection.

Contact author name, affiliation, email address:

A.M. James Shapiro, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.

E-mail address: jshapiro@ualberta.ca.

Funder: 

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest: 

A.M. James Shapiro reports a consulting or advisory role with ViaCyte Inc., Hemostemix Inc., and Aspect Biosystems Ltd. All remaining authors declare no conflicts of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

See the article:

Hefler, J., et al., Protective effects of cyclosporine and its analog NIM-811 in a murine model of hepatic ischemia-reperfusion injury, Liver Res, Volume 8, Issue 1, 2024, Pages 46-53, https://doi.org/10.1016/j.livres.2024.02.002.