Cyclosporin A (CsA) is a metabolite of the fungi Trichoderma polysporum. It is a cyclic polypeptide consisting of 9 amino-acids to inhibit nitric oxide synthesis induced by interleukin 1alpha, lipopolysaccharides and TNFα. Cyclosporin A (CsA) is an immunosuppressant that has revolutionized organ transplantation through its use in the prevention of graft rejection. CsA binds to cyclophilin and suppresses its proline rotamase activity. The CsA-cyclophilin complex inhibits calcineurin, a type 2B phosphatase. It is an important diagnostic tool for the characterization of permeability transition-related phenomena. It inhibits mitochondrial permeability transition pore opening however, pore inhibition becomes less efficient at increasing Ca²⁺ loads and inhibition is transient. Inhibits staurosporin-induced apoptosis in cultured neural cells and rotenone-induced apoptosis in PC-12 cells. Inhibits cytochrome c release from mitochondria. Inhibits nitric oxide (NO) synthesis.  >> Read More

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Cyclosporin A (CyA) is a powerful immunosuppressive agent whose lack of myelotoxicity makes it unique among nonsteroidal drugs currently given for immunosuppression. It has been used with initial success in recipients of kidney, liver, bone marrow and pancreas transplants, and it may also have clinical application in the treatment of autoimmune disorders. In regard to its use in transplant recipients, there are many remaining questions about its mechanism of action, the optimum dose, whether it should be used alone or with other immunosuppressants, whether it can suppress chronic rejection and what its long-term side effects may be. These questions can only be answered by further careful laboratory investigation and controlled clinical trials. Until then, CyA should only be administered in centres experienced in its use.

Laupacis, A., Keown, P. A., Ulan, R. A., McKenzie, N., & Stiller, C. R. (1982). Cyclosporin A: a powerful immunosuppressant. Canadian Medical Association Journal, 126(9), 1041.

CsA, FK-506, and rapamycin are microbial products with potent immunosuppressive properties that result primarily from a selective inhibition of T lymphocyte activation. Although chemically unrelated, CsA and FK-506 affect a similar subset of calcium-associated signaling events involved in the regulation of lymphokine gene expression, activation-driven T-cell death and exocytosis. Rapamycin has structural similarity with FK-506 but suppresses T-cell activation at a different level, mainly through inhibition of proliferation induced by growth-promoting lymphokines. CsA interacts with an abundant 17 kDa protein, termed cyclophilin, that possesses peptidyl-prolyl cis-trans isomerase (PPIase) activity. Additional, minor cyclophilin-like molecules have been identified. Both FK-506 and rapamycin interact with FKBP, a 12 kDa protein, which, although unrelated to cyclophilin, is also abundant and ubiquitous, has a similar enzymatic activity, and is a member of a larger family of FKBPs.

Sigal, N. H., & Dumont, F. J. (1992). Cyclosporin A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Annual review of immunology, 10(1), 519-560.

The site of action of the immunosuppressive drug cyclosporin A in in vitro cytotoxic allograft responses has been localized. General cytotoxic effects of the drug on proliferating T cells became apparent at concentrations of 500-1000 ng/ml, while selective effects were observed at concentrations of 10-100 ng/ml. The selective effects included a blockade of interleukin 2 release from activated T helper cells on the one hand and inhibition of interleukin 1 release from splenic adherent cells on the other. While cyclosporin A did not interfere with the intracellular events required for the activation and subsequent clonal expansion of alloreactive T cells, the lack of interleukin 1 and interleukin 2 induced by cyclosporin A results in an inability of T responder cells to mount cytotoxic allograft responses in vitro.

Bunjes, D., Hardt, C., Röllinghoff, M., & Wagner, H. (1981). Cyclosporin A mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of interleukin 1 and interleukin 2. European journal of immunology, 11(8), 657-661.