Dataset Information

Protective effect of the novel calcineurin inhibitor voclosporin in experimental colitis.

ABSTRACT:

Background and aims

Acute severe steroid-refractory ulcerative colitis remains a medically challenging condition with frequent need of surgery. It can be treated with the calcineurin inhibitor cyclosporine A with the need for therapeutic drug monitoring and significant toxicity. Recently, a novel calcineurin inhibitor, voclosporin, has been approved for the treatment of lupus nephritis with no need for therapeutic drug monitoring and an improved long-term safety profile. However, the therapeutic effect of voclosporin in acute severe steroid-refractory ulcerative colitis is still uncertain. We aimed to assess the therapeutic potential of voclosporin to ameliorate inflammation in an experimental model of colitis.

Methods

We used the dextran sodium sulfate-induced model of colitis in C57BL/6 J wildtype mice treated with either cyclosporine A, voclosporin or solvent control. We employed endoscopy, histochemistry, immunofluorescence, bead-based multiplex immunoassays and flow cytometry to study the therapeutic effect of calcineurin inhibitors in a preventive setting.

Results

Acute colitis was induced by dextran sodium sulfate characterized by weight loss, diarrhea, mucosal erosions and rectal bleeding. Both cyclosporine A and voclosporin strongly ameliorated the course of disease and reduced colitis severity in a similar manner.

Conclusion

Voclosporin was identified as biologically effective in a preclinical model of colitis and may be a potential therapeutic option in treating acute severe steroid-refractory ulcerative colitis.

SUBMITTER: Lindemann A

PROVIDER: S-EPMC10289195 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Protective effect of the novel calcineurin inhibitor voclosporin in experimental colitis.

Lindemann Aylin A Roth Dominik D Koop Kristina K Neufert Clemens C Zundler Sebastian S Atreya Raja R Neurath Markus F MF Leppkes Moritz M

Frontiers in medicine 20230609

<h4>Background and aims</h4>Acute severe steroid-refractory ulcerative colitis remains a medically challenging condition with frequent need of surgery. It can be treated with the calcineurin inhibitor cyclosporine A with the need for therapeutic drug monitoring and significant toxicity. Recently, a novel calcineurin inhibitor, voclosporin, has been approved for the treatment of lupus nephritis with no need for therapeutic drug monitoring and an improved long-term safety profile. However, the the ...[more]

PMID: 37358998

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Project description:BackgroundCalcineurin inhibitors (CNIs) affect kidney electrolyte handling and blood pressure (BP) through an effect on the distal tubule. The second-generation CNI voclosporin causes hypomagnesaemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally.MethodsRats were treated with voclosporin, tacrolimus or vehicle for 28 days. Dosing was based on a pilot experiment to achieve clinically therapeutic concentrations. Drug effects were assessed by electrolyte handling at day 18 and 28, thiazide testing at day 20, telemetric BP recordings and analysis of messenger RNA (mRNA) and protein levels of distal tubular transporters at day 28.ResultsCompared with vehicle, tacrolimus but not voclosporin significantly increased the fractional excretions of calcium (>4-fold), magnesium and chloride (both 1.5-fold) and caused hypomagnesaemia. Tacrolimus but not voclosporin significantly reduced distal tubular transporters at the mRNA and/or protein level, including the sodium-chloride cotransporter, transient receptor melastatin 6, transient receptor potential vanilloid 5, cyclin M2, sodium-calcium exchanger and calbindin-D28K. Tacrolimus but not voclosporin reduced the mRNA level and urinary excretion of epidermal growth factor. The saluretic response to hydrochlorothiazide at day 20 was similar in the voclosporin and vehicle groups, whereas it was lower in the tacrolimus group. The phosphorylated form of the sodium-chloride cotransporter was significantly higher at day 28 in rats treated with voclosporin than in those treated with tacrolimus. Tacrolimus transiently increased BP, whereas voclosporin caused a gradual but persistent increase in BP that was further characterized by high renin, normal aldosterone and low endothelin-1.ConclusionsIn contrast to tacrolimus, voclosporin does not cause hypercalciuria and hypomagnesaemia, but similarly causes hypertension. Our data reveal differences between the distal tubular effects of tacrolimus and voclosporin and provide a pathophysiological basis for the clinically observed differences between the two CNIs.

Project description:BackgroundThe improvement of colitis symptoms by treatment with IL-12/23 p40 neutralizing antibody should increase the muscle mass and the function of the sarcopenia phenotype.MethodsAn experimental colitis model was induced by oral administration of 2% dextran sulfate sodium (DSS) for 7 days. During induction of colitis, IL-12/23 p40 neutralizing antibody was injected twice on Days 3 and 5. The total body mass index was measured by dual-energy X-ray absorptiometry. The muscle function was measured by forelimb grip strength and fatigue running distance. The muscle fibre cross-sectional area (CSA) was calculated after the transverse section and haematoxylin and eosin staining, and gene expression was confirmed by RT-qPCR. Differentiated C2C12 cells were used as in vitro models and treated with recombinant IL12/23 proteins to mimic the enhanced cytokines in colitis.ResultsThe symptoms of colitis were alleviated by injection of IL-12/23 p40 neutralizing antibody compared with phosphate-buffered saline (PBS), and the disease activity index score was significantly lower on Day 8 (0.0 ± 0.00 of cont. vs. 11.3 ± 0.9 of DSS + PBS, P < 0.0001; DSS + PBS vs. 7.7 ± 1.25 of DSS + p40Ab, P < 0.0001). The CSA of the gastrocnemius and tibialis anterior muscle fibres decreased in mice with DSS-induced colitis (gastrocnemius, 1258.2 μm2 ± 176.45 of cont. vs. 640.1 μm2 ± 59.83 of DSS + PBS, P < 0.0001; tibialis anterior, 1251.8 μm2 ± 331.48 of cont. vs. 678.9 μm2 ± 67.59 of DSS + PBS, P < 0.0001), and the treatment of IL-12/23 p40 neutralizing antibody partially restored CSA of the gastrocnemius (640.1 μm2 ± 59.83 of DSS + PBS vs. 1062.0 μm2 ± 83.41 of DSS + p40Ab, P < 0.0001) and tibialis anterior (678.9 μm2 ± 67.59 of DSS + PBS vs. 1105.3 μm2 ± 143.15 of DSS + p40Ab, P = 0.0003).vs. 640.1 μm2 ± 59.83 of DSS + PBS, P < 0.0001) and tibialis anterior (1251.8 μm2 ± 331.48 of cont. vs. 678.9 μm2 ± 67.59 of DSS + PBS, P < 0.0001), and the treatment of IL-12/23 p40 neutralizing antibody partially restored CSA of the gastrocnemius (640.1 μm2 ± 59.83 of DSS + PBS vs. 1062.0 μm2 ± 83.41 of DSS + p40Ab, P < 0.0001) and tibialis anterior (678.9 μm2 ± 67.59 of DSS + PBS vs. 1105.3 μm2 ± 143.15 of DSS + p40Ab, P = 0.0003). In the evaluation of muscle function, grip strength and fatigue distance decreased by colitis were partially restored (grip strength: 139.9 g ± 5.38 of cont. vs. 83.9 g ± 5.48 of DSS + PBS, P < 0.0001; DSS + PBS vs. 118.6 g ± 4.05 of DSS + p40Ab, P < 0.0001; fatigue distance: 872.5 m ± 104.01 of cont. vs. 58.2 m ± 107.72 of DSS + PBS, P < 0.0001; DSS + PBS vs. 328.0 m ± 109.71 of DSS + p40Ab, P = 0.0015) by injection of IL-12/23 p40 neutralizing antibody.ConclusionsOur study demonstrates that Il-12/23 acts directly on muscle to induce atrophy, and the IL-12/23 p40 neutralizing antibody is effective not only in suppressing colitis but also in maintaining muscle mass and improving muscle function in an experimental colitis model.

Dataset Information

Protective effect of the novel calcineurin inhibitor voclosporin in experimental colitis.

Background and aims

Methods

Results

Conclusion

Publications

Protective effect of the novel calcineurin inhibitor voclosporin in experimental colitis.

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