Intrathecal cyclosporin prolongs survival of late-stage ALS mice.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by upper and lower motor neuron death with ascending paralysis leading to death. In a transgenic mouse model of ALS (SOD1-G93A) weakness appears at 3 months of age, and because of progressive paralysis leads to death by 5 months. Cyclosporin A (CsA) is well known, for its extracerebral effect, as an immunosuppressant in organ transplantation. When able to access the brain, CsA is an effective neuroprotective agent mainly due to its protection of mitochondria through inhibition of the mitochondrial permeability transition. CsA does not cross the intact blood-brain barrier and was in the present study delivered to the brain through an infusion into the lateral cerebral ventricle. Injections started at the onset of late disease when weakness of the hindlimbs was apparent. CsA treatment prolonged the survival of ALS transgenic mice as compared to vehicle-treated controls. This finding implicates mitochondrial function in ALS and may have significance for human disease.
Laboratory of Matrix Pathobiology, Pacific Biomedical Research Center, University of Hawaii, Honolulu 96822, USA. mkeep@aloha.net
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D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007278:Injections, Spinal; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000401:mortality; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D015996:Survival Rate
D007166:Immunosuppressive Agents; C000606290:SOD1 protein, human; D016572:Cyclosporine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1