Life span extension and reduced neuronal death after weekly intraventricular cyclosporin injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis.
OBJECTIVE
The authors investigated whether cyclosporin A (CsA), a cyclophilin ligand with mitochondrial permeability transition pore-blocking and calcineurin-inhibiting properties, affects motor function, neuronal death, and life span in the G93A transgenic mouse model of familial amyotrophic lateral sclerosis (FALS).


METHODS
The G93A mice received weekly intracerebroventricular injections of CsA (20 microg/mouse/week) starting at the age of 65 days, and physical performance on an exercise wheel was monitored beginning at 84 days of age. Mice were allowed to survive for clinical observation of body weight, hindlimb weakness, and life span or until a defined end stage or were killed at 110 days of age for histological analysis.


CONCLUSIONS
Treatment with CsA significantly delayed the onset of hindlimb weakness and also extended the time from its onset to paralysis. The overall life span of CsA-treated G93A mice was significantly extended, by 12% compared with vehicle-treated transgenic littermates. The CsA also prolonged physical performance on the exercise wheel and delayed weight loss. Histologically, there was significant preservation of both cervical and lumbar spine motor neurons and also tyrosine hydroxylase-positive dopaminergic substantia nigra neurons in 110-day-old CsA-treated mice compared with their transgenic littermates. The local administration of CsA directly into the brain ventricles is an effective means of central nervous system drug delivery (because CsA does not readily cross the blood-brain barrier), which in this study ameliorated clinical and neuropathological features of FALS in G93A mice. The remarkably low intrathecal CsA dose required for neuroprotection reduces potential adverse effects of systemic immunosuppression or nephrotoxicity seen with chronic systemic delivery of the drug.
Karlsson
Jenny
J
Laboratory of Matrix Pathobiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
Fong
Keith S K
KS
Hansson
Magnus J
MJ
Elmér
Eskil
E
Csiszar
Katalin
K
Keep
Marcus F
MF
D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects / Q000503:physiopathology; D001835:Body Weight / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D007276:Injections, Intraventricular; D008136:Longevity / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D018908:Muscle Weakness / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase; D013997:Time Factors
D018696:Neuroprotective Agents; D016572:Cyclosporine; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase