title: An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment.
abstract: To test potentially beneficial drugs to amyotrophic lateral sclerosis (ALS), we created an ALS mouse model with a permeable blood-brain barrier, by crossing the G93A-SOD1 transgenic mouse with a multiple drug resistance type 1a/b (mdr1a/b) gene knockout mouse. To validate the model, we administered cyclosporine A intraperitoneally to the mice. Cyclosporine A accumulated in the brain and spinal cord of this mouse model, whereas it was unable to penetrate the CNS of mdr1a/b wild-type animals. Systemic administration of cyclosporine A extended the life of the double-mutant male mice by approximately 12%. Surprisingly, the effect was more robust in male mice and only marginal in female mice. These results demonstrate the usefulness of this combined mouse model for the testing of potentially therapeutic drugs and support the role of mitochondrial-mediated apoptosis in the pathway to motor neuron death in SOD1-associated ALS.
authors.affiliation: Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida 33136, USA.
authors.forename: Ilias G
authors.initials: IG
authors.lastname: Kirkinezos
authors.forename: Dayami
authors.initials: D
authors.lastname: Hernandez
authors.forename: Walter G
authors.initials: WG
authors.lastname: Bradley
authors.forename: Carlos T
authors.initials: CT
authors.lastname: Moraes
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000367:Age Factors; D000409:Alanine / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005998:Glycine / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D011336:Probability; D012737:Sex Factors; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D014018:Tissue Distribution; D014316:Tritium / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C000606290:SOD1 protein, human; D014316:Tritium; D016572:Cyclosporine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000409:Alanine; D005998:Glycine