scholarly journals Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. Implications for the immunosuppressive and toxic effects of cyclosporin

1991 ◽  
Vol 274 (2) ◽  
pp. 611-614 ◽  
Author(s):  
E J Griffiths ◽  
A P Halestrap

The Ki values of cyclosporins A, G and H for the peptidyl-prolyl cis-trans isomerase (PPIase) of liver and heart mitochondria are about 2, 20 and 500 nM respectively. This parallels their profile as inhibitors of non-specific pore opening of mitochondria induced by supraphysiological Ca2+ concentrations. The novel immunosuppressant FK-506 gave little inhibition of either process at 5 microM. These data support our previous hypothesis [Halestrap & Davidson (1990) Biochem. J. 268, 153-160] that pore opening involves an interaction between matrix PPIase and the adenine nucleotide translocase. It is suggested that this model may help to clarify the mechanism of action of cyclosporin as an immunosuppressant and its toxic effects on the liver and kidney following prolonged therapy.

2006 ◽  
Vol 696 (1) ◽  
pp. 9-19 ◽  
Author(s):  
GREG WIEDERRECHT ◽  
ELSA LAM ◽  
SHIRLEY HUNG ◽  
MARY MARTIN ◽  
NOLAN SIGAL

1992 ◽  
Vol 2 (11) ◽  
pp. 616
Author(s):  
John J. Siekierka ◽  
Nolan H. Sigal

Diabetes ◽  
1993 ◽  
Vol 42 (12) ◽  
pp. 1753-1759 ◽  
Author(s):  
A. J. Krentz ◽  
B. Dousset ◽  
D. Mayer ◽  
P. McMaster ◽  
J. Buckels ◽  
...  

2000 ◽  
Vol 6 (3) ◽  
pp. C40-C40
Author(s):  
I GRAZIADEI ◽  
M LAIMER ◽  
K NACHBAUR ◽  
C EBENBICHLER ◽  
A KONIGSRAINER ◽  
...  

2020 ◽  
Vol 28 (3) ◽  
pp. 15-20
Author(s):  
Viktoria N. Germanova ◽  
Natal'ya N. Sarbaeva ◽  
Elena V. Karlova ◽  
Larisa T. Volova ◽  
Irina F. Nefyodova ◽  
...  

Prolonged use of immunosuppressants with a selective mechanism of action is a promising strategy in the prevention of postoperative scarring in glaucoma surgery. In order to assess the cellular response of eye tissues to the implantation of bioresorbable drains saturated with cyclosporin A or everolimus, a filter-type hypotensive operation with implantation of polylactide-based drains was simulated in 12 rabbits. Drainages implanted in rabbits of the two experimental groups under study were pre-saturated with either cyclosporin A or everolimus. The control group consisted of animals that were implanted with drains not saturated with any drugs. On the 7th day after the operation, the animals were taken out of the experiment, the eyeballs were enucleated, and histological preparations stained with hematoxylin and eosin, as well as hematoxylin and Picrosirius-red were prepared. Using a score on a scale from 0 to 5, the cellular composition within the drainage material, the intensity of collagen synthesis in the drainage, the thickness of the capsule around the drainage, and the number of blood vessels were analyzed. In comparison with the control group, the study groups showed a significantly lower amount of mononuclear cells, fibroblasts and giant cells of foreign bodies, as well as a lower thickness of the capsules surrounding the drainage, up to their complete absence. In addition, the intensity of collagen synthesis inside the drainage material of the studied groups was significantly lower. The drains of the everolimus group were characterized by an extremely low density of viable cellular elements inside the implanted material and a complete absence of collagen. At the same time, no toxic effect of the substance on the surrounding tissues was found. Thus, the saturation of bioresorbable drainages based on polylactide with cyclosporin A and everolimus contributed to a decrease in the intensity of the formation of connective tissue elements both inside and around the drainage in the early postoperative period.


1993 ◽  
Vol 79 (5) ◽  
pp. 710-715 ◽  
Author(s):  
Kazuya Nagata ◽  
Tomio Sasaki ◽  
Junichi Iwama ◽  
Takashi Mori ◽  
Shoko Iwamoto ◽  
...  

✓ In order to clarify the possible role of immunological reaction in the pathogenesis of cerebral vasospasm, the authors examined the prophylactic effect of the immunosuppressant agents FK-506 and cyclosporin A on chronic vasospasm in a canine two-hemorrhage model. While a mean constriction of the basilar artery to 81.0% ± 4.0% (± standard error of the mean) occurred on Day 2 and to 63.8% ± 3.5% on Day 7 in the untreated group, constriction to 77.9% ± 3.4% on Day 2 and 62.8% ± 3.0% on Day 7 was demonstrated in the FK-506-treated group (difference not significant). This tendency was also noted in the cyclosporin A-treated group, with basilar artery constriction to 81.8% ± 3.7% and 56.3% ± 2.7%, respectively (difference not significant). The histological changes of the basilar artery, including corrugation of the elastic lamina, detachment of endothelial cells, and vacuolar formation in the smooth-muscle layer were not different in the two treated groups and the one control group. Since these immunosuppressant agents are known to inhibit the release of interleukin-2 (IL-2), the level of IL-2 was examined in the cerebrospinal fluid of patients with cerebral vasospasm. While interleukin-1 gradually increased in level as time passed, the level of IL-2 was consistently low during the course of the study, indicating less participation of IL-2 in the pathogenesis of cerebral vasospasm. This clinical observation matched the experimental results. The authors conclude that cell-mediated immunoreaction, initiated mainly by IL-2, plays little role in the pathogenesis of cerebral vasospasm.


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