Abstract
Cyclosporin A (CsA) is highly neuroprotective in several animal models of acute neurological damage and neurodegenerative disease with inhibition of the mitochondrial permeability transition (mPT) having emerged as a possible mechanism for the observed neuroprotection. In the present study, we have evaluated two new nonimmunosuppressive cyclosporin analogs NIM811 (Novartis) and UNIL025 (Debiopharm) for their ability to inhibit mPT in rat brain-derived mitochondria. Both NIM811 and UNIL025 were found to be powerful inhibitors of calcium-induced mitochondrial swelling under energized and deenergized conditions, and the maximal effects were identical to those of native CsA. The potencies of mPT inhibition by NIM811 and UNIL025 were stronger, with almost one order of magnitude higher potency for UNIL025 compared to CsA, correlating to their respective inhibitory action of cyclophilin activity. These compounds will be instrumental in the evaluation of mPT as a central target for neuroprotection in vivo.
Similar content being viewed by others
REFERENCES
Alves, O., Tolias, C. M., Lewis, C., Hayes, R., Choi, S., Gilman, C., Enriquez, P., Povlishock, J., and Bullock, M. R. (2003). J. Neuro-trauma 20, 1125. (NNS Symposium abstract).
Bambrick, L., Kristian, T., and Fiskum, G. (2004). Neurochem. Res. 29, 601–608
Begley, D. J., Squires, L. K., Zlokovic, B. V., Mitrovic, D. M., Hughes, C. C., Revest, P. A., and Greenwood, J. (1990). J. Neurochem. 55, 1222–1230.
Billich, A., Hammerschmid, F., Peichl, P., Wenger, R., Zenke, G., Quesniaux, V., and Rosenwirth, B. (1995). J. Virol. 69, 2451–2461.
Borel, J. F., Baumann, G., Chapman, I., Donatsch, P., Fahr, A., Mueller, E. A., and Vigouret, J. M. (1996). Adv. Pharmacol. 35, 115–246.
Brophy, G. M., Bullock, M. R., Tolias, C. M., Alves, O., Enriquez, P., and Gilman, C. (2003). J. Neurotrauma 20, 1125. (NNS Symposium abstract).
Crompton, M. (1999). Biochem. J. 341, 233–249.
Friberg, H., and Wieloch, T. (2002). Biochimie 84, 241–250.
Friberg, H., Connern, C., Halestrap, A. P., and Wieloch, T. (1999). J. Neurochem. 72, 2488–2497.
Halestrap, A. P., McStay, G. P., and Clarke, S. J. (2002). Biochimie 84, 153–166.
Hansson, M. J., Persson, T., Friberg, H., Keep, M. F., Rees, A., Wieloch, T., and Elmér, E. (2003). Brain Res. 960, 99–111.
Hansson, M. J., Månsson, R., Mattiasson, G., Ohlsson, J., Karlsson, J., Keep, M. F., and Elmér E. (2004). J. Neurochem. 89, 715–729.
Keep, M., Elmér, E., Fong, K. S., and Csiszar, K. (2001). Brain Res. 894, 327–331.
Keep, M. F., Uchino, H., and Elmér, E. (2003). In Immunosuppressant Analogs in Neuroprotection (Borlongan, C. V., Isacson, O., and Sanberg, P. R., eds.), Humana Press, Totowa, pp. 3–32.
Lemasters, J. J., Nieminen, A. L., Qian, T., Trost, L. C., Elmore, S. P., Nishimura, Y., Crowe, R. A., Cascio, W. E., Bradham, C. A., Brenner, D. A., and Herman, B. (1998). Biochim. Biophys. Acta 1366, 177–196.
Mattiasson, G., Friberg, H., Hansson, M., Elmér, E., and Wieloch, T. (2003). J. Neurochem. 87, 532–544.
Nicolli, A., Basso, E., Petronilli, V., Wenger, R. M., and Bernardi, P. (1996). J. Biol. Chem. 271, 2185–2192.
Okonkwo, D. O., Melon, D. E., Pellicane, A. J., Mutlu, L. K., Rubin, D. G., Stone, J. R., and Helm, G. A. (2003). Neuroreport 14, 463–466.
Petronilli, V., Nicolli, A., Costantini, P., Colonna, R., and Bernardi, P. (1994). Biochim. Biophys. Acta 1187, 255–259.
Rosenwirth, B., Billich, A., Datema, R., Donatsch, P., Hammerschmid, F., Harrison, R., Hiestand, P., Jaksche, H., Mayer, P., Peichl, P., et al. (1994). Antimicrob. Agents Chemother. 38, 1763–1772.
Sims, N. (1990). J. Neurochem. 55, 698–707.
Sullivan, P. G., Rabchevsky, A. G., Hicks, R. R., Gibson, T. R., Fletcher-Turner, A., and Scheff, S. W. (2000). Neuroscience 101, 289–295.
Tsuji, A., Tamai, I., Sakata, A., Tenda, Y., and Terasaki, T. (1993). Biochem. Pharmacol. 46, 1096–1099.
Uchino, H., Elmér, E., Uchino, K., Lindvall, O., and Siesjö, B. K. (1995). Acta Physiol. Scand. 155, 469–471.
Waldmeier, P. C., Feldtrauer, J. J., Qian, T., and Lemasters, J. J. (2002). Mol. Pharmacol. 62,22–29.
Waldmeier, P. C., Zimmermann, K., Qian, T., Tintelnot-Blomley, M., and Lemasters, J. J. (2003). Curr. Med. Chem. 10, 1485–1506.
Yoshimoto, T., and Siesjö, B. K. (1999). Brain Res. 839, 283–291.
Zamzami, N., and Kroemer, G. (2001). Nat. Rev. Mol. Cell. Biol. 2, 67–71.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hansson, M.J., Mattiasson, G., Månsson, R. et al. The Nonimmunosuppressive Cyclosporin Analogs NIM811 and UNIL025 Display Nanomolar Potencies on Permeability Transition in Brain-Derived Mitochondria. J Bioenerg Biomembr 36, 407–413 (2004). https://doi.org/10.1023/B:JOBB.0000041776.31885.45
Issue Date:
DOI: https://doi.org/10.1023/B:JOBB.0000041776.31885.45