title: Evaluation of the protective effects of cyclosporin a and FK506 on abnormal cytosolic and mitochondrial Ca²⁺ dynamics during ischemia and exposure to high glutamate concentration in mouse brain slice preparations.
abstract: We examined the protective effects of the immunosuppressants cyclosporin A (CsA) and FK506 on abnormal cytosolic Ca²⁺ ([Ca²⁺]c) and mitochondrial Ca²⁺ concentration ([Ca²⁺]m) dynamics induced by ischemia or high L-glutamate concentration in mouse brain slice preparations. We used fura-4F and rhod-2 as indicators for [Ca²⁺]c and [Ca²⁺]m, respectively, in their acetoxymethylester form. Slice preparations loaded with either of these two indicators were exposed to ischemic artificial cerebrospinal fluid (oxygen- and glucose-deprived medium) for 12 min or to aerobic medium with high L-glutamate concentration (isotonic 20 mM L-glutamate) for 5 min. CsA (1 - 10 μM) showed significant protective effects on the maximum increase in ischemia-induced [Ca²⁺]c and [Ca²⁺]m. FK506 (10 μM) showed significant protective effects on the [Ca²⁺]m increase, but not on the ischemia-induced [Ca²⁺]c increase. Both immunosuppressants showed almost equal protective effects on the [Ca²⁺]c and [Ca²⁺]m increases induced by high L-glutamate concentration. These results suggest that the protective effects of CsA and FK506 on Ca²⁺ overloading may be dependent upon the common pharmacological sites of actions relating to their effects as immunosuppressants. The small, but significant depressant effects of these drugs could give us important clues for rescuing critical brain damage induced by Ca²⁺ overloading.
authors.affiliation: Department of Emergency and Critical Care Medicine and Neurosurgery, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tanoue
authors.forename: Erika
authors.initials: E
authors.lastname: Hasegawa
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Shouichi
authors.initials: S
authors.lastname: Ohta
authors.forename: Akibumi
authors.initials: A
authors.lastname: Omi
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kudo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchino
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D001931:Brain Mapping; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009994:Osmolar Concentration; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D016572:Cyclosporine; D016559:Tacrolimus