Cyclosporin D

Cyclosporin D is an immunosuppressive agent [1].

Cyclosporin D (CsD) is an analogue of cyclosporine A with weak immunosuppressive activity. Cyclosporin D has been used as an internal standard for the quantification of cyclosporin A. In human multidrug-resistant ovarian cancer cells, cyclosporin D significantly overcame adriamycin resistance [2]. In lymphocyte, CsD weakly inhibited PHA-, PWM-, and PMA + Ca2+-induced cell proliferation [3].

In mice, CsD inhibited edema in mouse ear and alkaline phosphatase activity in mouse skin induced by TPA by 98% and 88%, respectively. In cytosol of mouse pancreas, CsD inhibited the Ca2+/calmodulin-dependent phosphorylation of the elongation factor 2 (EF-2) and the TPA-induced increase of EF-2 [1]. Cyclosporin D was effective in inhibiting P. falciparum parasite in vitro and P. berghei malaria parasite development in vivo when administered orally [4].

References:
[1].  Gschwendt M, Kittstein W, Marks F. The weak immunosuppressant cyclosporine D as well as the immunologically inactive cyclosporine H are potent inhibitors in vivo of phorbol ester TPA-induced biological effects in mouse skin and of Ca2+/calmodulin dependent EF-2 phosphorylation in vitro. Biochem Biophys Res Commun, 1988, 150(2): 545-551.
[2].  Mizuno K, Furuhashi Y, Misawa T, et al. Modulation of multidrug resistance by immunosuppressive agents: cyclosporin analogues, FK506 and mizoribine. Anticancer Res, 1992, 12(1): 21-25.
[3].  Sadeg N, Pham-Huy C, Rucay P, et al. In vitro and in vivo comparative studies on immunosuppressive properties of cyclosporines A, C, D and metabolites M1, M17 and M21. Immunopharmacol Immunotoxicol, 1993, 15(2-3): 163-177.
[4].  Uadia PO1, Ezeamuzie IC, Ladan MJ, et al. Antimalarial activity of cyclosporins A, C and D. Afr J Med Med Sci, 1994, 23(1): 47-51.

Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor.[Pubmed:24295872]

J Hepatol. 2014 Apr;60(4):723-31.

BACKGROUND & AIMS: Chronic hepatitis B and hepatitis D are global health problems caused by the human hepatitis B and hepatitis D virus. The myristoylated preS1 domain of the large envelope protein mediates specific binding to hepatocytes by sodium taurocholate co-transporting polypeptide (NTCP). NTCP is a bile salt transporter known to be inhibited by cyclosporin A. This study aimed to characterize the effect of cyclosporin A on HBV/HDV infection. METHODS: HepaRG cells, primary human hepatocytes, and susceptible NTCP-expressing hepatoma cell lines were applied for infection experiments. The mode of action of cyclosporin A was studied by comparing the effect of different inhibitors, cyclophilin A/B/C-silenced cell lines as well as NTCP variants and mutants. Bile salt transporter and HBV receptor functions were investigated by taurocholate uptake and quantification of HBVpreS binding. RESULTS: Cyclosporin A inhibited hepatitis B and D virus infections during and--less pronounced--prior to virus inoculation. Binding of HBVpreS to NTCP was blocked by cyclosporin A concentrations at 8 muM. An NTCP variant deficient in HBVpreS binding but competent for bile salt transport showed resistance to cyclosporin A. Silencing of cyclophilins A/B/C did not abrogate transporter and receptor inhibition. In contrast, tacrolimus, a cyclophilin-independent calcineurin inhibitor, was inactive. CONCLUSIONS: HBV and HDV entry via sodium taurocholate co-transporting polypeptide is inhibited by cyclosporin A. The interaction between the drug and the viral receptor is direct and overlaps with a functional binding site of the preS1 domain, which mediates viral entry.

Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury.[Pubmed:24603333]

Cell Death Dis. 2014 Mar 6;5:e1105.

Cyclosporin A (CsA) inhibits the opening of the mitochondrial permeability transition pore (MPTP) by interacting with cyclophilin D (CypD) and ameliorates neuronal cell death in the central nervous system against ischemic injury. However, the molecular mechanisms underlying CypD/MPTP opening-mediated cell death in ischemic retinal injury induced by acute intraocular pressure (IOP) elevation remain unknown. We observed the first direct evidence that acute IOP elevation significantly upregulated CypD protein expression in ischemic retina at 12 h. However, CsA prevented the upregulation of CypD protein expression and promoted retinal ganglion cell (RGC) survival against ischemic injury. Moreover, CsA blocked apoptotic cell death by decreasing cleaved caspase-3 protein expression in ischemic retina. Of interest, although the expression level of Bcl-xL protein did not show a significant change in ischemic retina treated with vehicle or CsA at 12 h, ischemic damage induced the reduction of Bcl-xL immunoreactivity in RGCs. More importantly, CsA preserved Bcl-xL immunoreactivity in RGCs of ischemic retina. In parallel, acute IOP elevation significantly increased phosphorylated Bad (pBad) at Ser112 protein expression in ischemic retina at 12 h. However, CsA significantly preserved pBad protein expression in ischemic retina. Finally, acute IOP elevation significantly increased mitochondrial transcription factor A (Tfam) protein expression in ischemic retina at 12 h. However, CsA significantly preserved Tfam protein expression in ischemic retina. Studies on mitochondrial DNA (mtDNA) content in ischemic retina showed that there were no statistically significant differences in mtDNA content among control and ischemic groups treated with vehicle or CsA. Therefore, these results provide evidence that the activation of CypD-mediated MPTP opening is associated with the apoptotic pathway and the mitochondrial alteration in RGC death of ischemic retinal injury. On the basis of these observations, our findings suggest that CsA-mediated CypD inhibition may provide a promising therapeutic potential for protecting RGCs against ischemic injury-mediated mitochondrial dysfunction.

Protective effect of 2-deoxy-D-glucose on the cytotoxicity of cyclosporin A in vitro.[Pubmed:25976221]

Mol Med Rep. 2015 Aug;12(2):2814-20.

The present study aimed to investigate the mechanism underlying the protective effect of 2-deoxy-D-glucose (2-DG) on the cytotoxicity of cyclosporin A (CsA) in vitro using NRK-52E cells. Staining with Hoechst 33342/propidium iodide prior to flow cytometric analysis was performed to assess the rate of cellular apoptosis and necrosis induced by CsA. The expression levels of lactate dehydrogenase (LDH), caspase 3, receptor-interacting protein kinase 3 (RIP3), reactive oxygen species (ROS), glutathione (GSH) and malondialdehyde (MDA) were detected using colorimetry, ELISA, western blotting or flow cytometric analysis to determine the protective effects of 2-DG on CsA-induced cell death. The results demonstrated that 2-DG inhibited the release of LDH, the activation of caspase 3 and the generation of ROS induced by CsA, but had no effect on the expression of RIP3. Treatment with 2-DG increased the expression of GSH and decreased the expression of MDA in dose-dependent manner, and reduced the rate of the cellular apoptosis and necrosis induced by CsA. Therefore, 2-DG inhibited CsA-induced cellular apoptosis and necrosis, possibly by reducing the production of ROS. Inhibiting the activation of caspase 3 is one of the protective mechanisms of 2-DG, however, the expression of RIP3 remained unaltered following treatment with 2-DG. Whether 2-DG inhibits the CsA-induced necrosis and apoptosis by inhibiting the RIP3 signaling pathway remains to be elucidated.

Novel effect of the inhibitor of mitochondrial cyclophilin D activation, N-methyl-4-isoleucine cyclosporin, on renal calcium crystallization.[Pubmed:24661223]

Int J Urol. 2014 Jul;21(7):707-13.

OBJECTIVES: To experimentally evaluate the clinical application of N-methyl-4-isoleucine cyclosporin, a novel selective inhibitor of cyclophilin D activation. METHODS: In vitro, cultured renal tubular cells were exposed to calcium oxalate monohydrate crystals and treated with N-methyl-4-isoleucine cyclosporin. The mitochondrial membrane was stained with tetramethylrhodamine ethyl ester perchlorate and observed. In vivo, Sprague-Dawley rats were divided into four groups: a control group, an ethylene glycol group (administration of ethylene glycol to induce renal calcium crystallization), a N-methyl-4-isoleucine cyclosporin group (administration of N-methyl-4-isoleucine cyclosporin) and an ethylene glycol + N-methyl-4-isoleucine cyclosporin group (administration of ethylene glycol and N-methyl-4-isoleucine cyclosporin). Renal calcium crystallization was evaluated using Pizzolato staining. Oxidative stress was evaluated using superoxide dismutase and 8-hydroxy-deoxyguanosine. Mitochondria within renal tubular cells were observed by transmission electron microscopy. Cell apoptosis was evaluated using cleaved caspase-3. RESULTS: In vitro, calcium oxalate monohydrate crystals induced depolarization of the mitochondrial membrane potential, which was remarkably prevented by N-methyl-4-isoleucine cyclosporin. In vivo, ethylene glycol administration induced renal calcium crystallization, oxidative stress, mitochondrial collapse and cell apoptosis in rats, which were significantly prevented by N-methyl-4-isoleucine cyclosporin. CONCLUSIONS: Herein we first report a new treatment agent determining renal calcium crystallization through cyclophilin D activation.

Cyclosporin D, a metabolite of Cyclosporin A, is a weak immunosuppressant. Cyclosporin D is used as internal standard for quantification of Cyclosporin A. Cyclosporin A is a potent immunosuppressant drug, suppress T cell activation by inhibiting calcineurin and the calcineurin-dependent transcription factors nuclear factor of activated T cells (NFAc).

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