title: Effects of cyclosporine A and its immunosuppressive or non-immunosuppressive derivatives [D-Ser]8-CsA and Cs9 on mitochondria from different brain regions.
abstract: We studied the functional properties of isolated brain mitochondria (BM) prepared from total rat brain (BM(total)) or from cerebral subregions under basal and Ca(2+) overload conditions in order to evaluate the effects of cyclosporine A (CsA) in a regiospecific manner. CsA-induced effects were compared with those of two derivatives-the none-immunosuppressive [O-(NH(2)(CH2)(5)NHC(O)CH(2))-D-Ser](8)-CsA (Cs9) and its congener, the immunosuppressive [D-Ser](8)-CsA. The glutamate/malate-dependent state 3 respiration of mitochondria (state 3(glu/mal)) differed in region-specific manner (cortex > striatum = cerebellum > substantia nigra > hippocampus), but was significantly increased by 1μM CsA (+21±5%) in all regions. Ca(2+) overload induced by addition of 20μM Ca(2+) caused a significant decrease of state 3(glu/mal) (-45 to -55%) which was almost completely prevented in the presence of 1μM CsA, 1μM Cs9 or 1μM [D-Ser](8)-CsA. Mitochondrial Ca(2+) accumulation thresholds linked to permeability transition (PT) as well as the rate and completeness of mitochondrial Ca(2+) accumulation differed between different brain regions. For the first time, we provide a detailed, regiospecific analysis of Ca(2+)-dependent properties of brain mitochondria. Regardless of their immunosuppressive impact, CsA and its analogues improved mitochondrial functional properties under control conditions. They also preserved brain mitochondria against Ca(2+) overload-mediated PT and functional impairments. Since Cs9 does not mediate immunosuppression, it might be used as a more specific PT inhibitor than CsA.
authors.affiliation: Leibniz Institute for Neurobiology, Department Behavioral Neurology, Brenneckestr. 6, D-39118 Magdeburg, Germany.
authors.forename: Zemfira Z
authors.initials: ZZ
authors.lastname: Gizatullina
authors.forename: Timur M
authors.initials: TM
authors.lastname: Gaynutdinov
authors.forename: Hanno
authors.initials: H
authors.lastname: Svoboda
authors.forename: Doreen
authors.initials: D
authors.lastname: Jerzembek
authors.forename: Annette
authors.initials: A
authors.lastname: Knabe
authors.forename: Stefan
authors.initials: S
authors.lastname: Vielhaber
authors.forename: Miroslav
authors.initials: M
authors.lastname: Malesevic
authors.forename: Hans-Jochen
authors.initials: HJ
authors.lastname: Heinze
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.forename: Frank
authors.initials: F
authors.lastname: Striggow
authors.forename: Frank N
authors.initials: FN
authors.lastname: Gellerich
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D016572:Cyclosporine / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D016572:Cyclosporine; D002118:Calcium