https://www.ajkd.org/article/S0272-6386(00)70348-9/pdf

Nephrotoxicity of immunosuppressive drugs: Long-term consequences and challenges for the future

Publisher Summary The powerful immunosuppressive activity of ciclosporin (CS), which is apparently restricted at the cellular level of certain T lymphocytes, is recognized as a breakthrough in immunopharmacology. CS is a potent inhibitor of chronic or immune-mediated inflammatory reactions, but has no effect in models of acute inflammation. Its importance for exploring the pathogenesis and treatment of some acute and chronic inflammatory diseases, generally grouped as suspected autoimmune.diseases, is clearly emerging in the clinic. The use of CS in the treatment of several such diseases has revealed its potential to counteract the imbalance of the immune system by improving the condition of both experimental animals and patients. After a difficult learning process in which the efficacy and the side effects of the drug were explored, CS has proved to be of permanent clinical value and has, in consequence, revitalized the field of organ transplantation. In contrast to classical immunosuppressants, CS exerts a specific action on lymphocytes but is not detrimental to the functions of phagocytes or hemopoietic stem cells. Besides being an immunosuppressive drug, CS is also widely used as an experimental probe in basic research. While evidence for this concept is compelling, various phenomena in vivo are not readily explained by this model. This review shows that in vitro several pathways can be used to induce gene transcription in lymphocytes. Whether the alternative pathways, that is, those bypassing the T-cell receptor, are also relevant in vivo remains another question. However, only the pathways involving mobilization of intracellular calcium are CS-sensitive.

In Vivo Pharmacological Effects of Ciclosporin and Some Analogues

Objective and Design: Cyclosporin, FK-506 and rapamycin have similar but distinct modes of interaction with cyclophilins, calcineurins and transcription factors. These immunosuppressive drugs have also been shown to inhibit cytotoxic and inflammatory responses in macrophage. Therefore, we evaluated the mechanism of action of these drugs on iNOS and COX-2 expression by macrophages, the products of which (NO and PGE2) have cytotoxic and pro-inflammatory activities.¶Materials and Methods: The murine macrophage cell line RAW 264.7 was grown as monolayer cultures. The effects of pharmacologically relevant concentrations of cyclosporin, rapamycin and FK-506 were evaluated in the presence and absence of lipopolysaccharide (LPS) which is a known inducer of iNOS and COX-2. Subsequently the expression of iNOS and COX-2 were analyzed by Western and Northern analysis. The production of NO and PGE2 were assayed by Greiss and RIA respectively.¶Results: Cyclosporin (1-5 μg/ml) and rapamycin (1.0-10 nM) but not FK-506 (5-10 nM) inhibited both iNOS and COX-2 expression at mRNA level which led to significant inhibition of NO and PGE2 production.¶Conclusion: These studies characterize differential mechanistic capacity of the immunophilin-binding immunosuppressive drugs (comparable to hydrocortisone) to inhibit both iNOS and COX-2 expression. Inhibition of iNOS and COX-2 mRNA accumulation by cyclosporin and rapamycin seem to be distinct. These studies also highlight potential anti-inflammatory properties of these drugs in addition to their known immunosuppressive activity.¶

Differential anti-inflammatory effects of immunosuppressive drugs: cyclosporin, rapamycin and FK-506 on inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and PGE2 production.

Background and purpose:

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by the absence of the cytoskeletal protein dystrophin. This leads to muscle cell death accompanied by chronic inflammation. Cyclosporin A (CsA) is a powerful immunosuppressive drug, which has been proposed for DMD treatment. CsA also directly regulates the mitochondrial permeability transition pore (mPTP), which participates in cell death pathways through the inhibition of cyclophilin D. Here, we evaluated whether Debio 025, a cyclophilin inhibitor with no immunosuppressive activity, improves the dystrophic condition in a mouse model of DMD, through regulation of mPTP.



Experimental approach:

The potency of Debio 025 to protect mouse dystrophic cells against mitochondria-mediated death was assessed by caspase-3 activity and calcium retention capacity assays. Mdx5Cv mice (3-week-old) were treated daily by gavage for 2 weeks with Debio 025 (10, 30 or 100 mg kg−1), CsA (10 mg kg−1) or placebo. The effects on muscle necrosis and function were measured.



Key results:

In vitro investigations showed protective effect of low concentrations of Debio 025 against cell death. Histology demonstrated that Debio 025 partially protected the diaphragm and soleus muscles against necrosis (10 and 100 mg kg−1, respectively). Hindlimb muscles from mice receiving Debio 025 at 10 mg kg−1 relaxed faster, showed alteration in the stimulation frequency-dependent recruitment of muscle fibres and displayed a higher resistance to mechanical stress.



Conclusions and implications:

Debio 025 partially improved the structure and the function of the dystrophic mouse muscle, suggesting that therapies targeting the mPTP may be helpful to DMD patients.



British Journal of Pharmacology (2008) 155, 574–584; doi:10.1038/bjp.2008.285; published online 21 July 2008

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/bjp.2008.285

Investigation of Debio 025, a cyclophilin inhibitor, in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy

Inhibition of cAMP-responsive element-mediated gene transcription by cyclosporin A and FK506 after membrane depolarization.

Pharmacology of cyclosporine (sandimmune). VII. Pathophysiology and toxicology of cyclosporine in humans and animals.

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Pharmacology of cyclosporine (sandimmune). VII. Pathophysiology and toxicology of cyclosporine in humans and animals.