Journal of Bioenergetics and Biomembranes

, Volume 36, Issue 4, pp 407–413

The Nonimmunosuppressive Cyclosporin Analogs NIM811 and UNIL025 Display Nanomolar Potencies on Permeability Transition in Brain-Derived Mitochondria

  • Magnus J. Hansson
  • Gustav Mattiasson
  • Roland Månsson
  • Jenny Karlsson
  • Marcus F. Keep
  • Peter Waldmeier
  • Urs T. Ruegg
  • Jean-Maurice Dumont
  • Kamel Besseghir
  • Eskil Elmér
Article

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.

Cell death apoptosis neuron ischemia neurodegeneration traumatic brain injury amyotrophic lateral sclerosis cyclophilin mitochondrial permeability transition flow cytometry 

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Copyright information

© Springer Science+Business Media, Inc. 2004

Authors and Affiliations

  • Magnus J. Hansson
    • 1
    • 2
  • Gustav Mattiasson
    • 1
  • Roland Månsson
    • 1
    • 3
  • Jenny Karlsson
    • 4
  • Marcus F. Keep
    • 5
  • Peter Waldmeier
    • 6
  • Urs T. Ruegg
    • 7
  • Jean-Maurice Dumont
    • 8
  • Kamel Besseghir
    • 8
  • Eskil Elmér
    • 1
  1. 1.Laboratory for Experimental Brain Research, Wallenberg Neuroscience CenterLund UniversityLundSweden
  2. 2.Department of Internal MedicineRyhov HospitalJönköpingSweden
  3. 3.Department of NeurologyMalmö University HospitalSweden
  4. 4.Community Environmental Health Program, Department of Internal MedicineUniversity ofNew Mexico, AlbuquerqueNew Mexico
  5. 5.Division of NeurosurgeryUniversity of New MexicoAlbuquerqueNew Mexico
  6. 6.Department of NeuroscienceNovartis Institute for Biomedical ResearchBaselSwitzerland
  7. 7.Pharmacology Group, School of PharmacyUniversity of LausanneSwitzerland
  8. 8.Debiopharm S. A.LausanneSwitzerland

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