Effects of cyclosporine A and its immunosuppressive or non-immunosuppressive derivatives [D-Ser]8-CsA and Cs9 on mitochondria from different brain regions

We studied the functional properties of isolated brain mitochondria (BM) prepared from total rat brain (BMtotal) or from cerebral subregions under basal and Ca2+ 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-(NH2(CH2)5NHC(O)CH2)-D-Ser]8-CsA (Cs9) and its congener, the immunosuppressive [D-Ser]8-CsA. The glutamate/malate-dependent state 3 respiration of mitochondria (state 3glu/mal) differed in region-specific manner (cortex > striatum = cerebellum > substantia nigra > hippocampus), but was significantly increased by 1 μM CsA (+ 21 ± 5%) in all regions. Ca2+ overload induced by addition of 20 μM Ca2+ caused a significant decrease of state 3glu/mal (−45 to −55%) which was almost completely prevented in the presence of 1 μM CsA, 1 μM Cs9 or 1 μM [D-Ser]8-CsA. Mitochondrial Ca2+ accumulation thresholds linked to permeability transition (PT) as well as the rate and completeness of mitochondrial Ca2+ accumulation differed between different brain regions. For the first time, we provide a detailed, regiospecific analysis of Ca2+-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 Ca2+ overload-mediated PT and functional impairments. Since Cs9 does not mediate immunosuppression, it might be used as a more specific PT inhibitor than CsA.