title: The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria.
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.
authors.affiliation: Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University, BMC A13, SE-221 84 Lund, Sweden.
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Hansson
authors.forename: Gustav
authors.initials: G
authors.lastname: Mattiasson
authors.forename: Roland
authors.initials: R
authors.lastname: Månsson
authors.forename: Jenny
authors.initials: J
authors.lastname: Karlsson
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Keep
authors.forename: Peter
authors.initials: P
authors.lastname: Waldmeier
authors.forename: Urs T
authors.initials: UT
authors.lastname: Ruegg
authors.forename: Jean-Maurice
authors.initials: JM
authors.lastname: Dumont
authors.forename: Kamel
authors.initials: K
authors.lastname: Besseghir
authors.forename: Eskil
authors.initials: E
authors.lastname: Elmér
mesh_terms: D000818:Animals; D002118:Calcium / Q000008:administration & dosage*; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008832:Microchemistry / Q000379:methods; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D051381:Rats
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D002118:Calcium; C499715:alisporivir