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Life span extension and reduced neuronal death after weekly intraventricular cyclosporin injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis

Karlsson, Jenny; Fong, KSK; Hansson, Magnus LU ; Elmer, Eskil LU ; Csiszar, K and Keep, MF (2004) In Journal of Neurosurgery 101(1). p.128-137
Abstract
Object. 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 mug/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.... (More)
Object. 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 mug/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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Parkinson disease, neurodegenerative disease, amyotrophic lateral sclerosis, mitochondria, superoxide dismutase, G93A transgenic mouse
in
Journal of Neurosurgery
volume
101
issue
1
pages
128 - 137
publisher
American Association of Neurosurgeons
external identifiers
  • wos:000222398700020
  • pmid:15255263
  • scopus:3042511616
ISSN
0022-3085
language
English
LU publication?
yes
id
55737212-537e-46a3-a82d-77034c82eee7 (old id 273481)
alternative location
http://jnsonline.org/jns/issues/v101n1/pdf/n1010128.pdf
date added to LUP
2007-10-23 15:55:07
date last changed
2017-01-01 06:38:41
@article{55737212-537e-46a3-a82d-77034c82eee7,
  abstract     = {Object. 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 mug/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.},
  author       = {Karlsson, Jenny and Fong, KSK and Hansson, Magnus and Elmer, Eskil and Csiszar, K and Keep, MF},
  issn         = {0022-3085},
  keyword      = {Parkinson disease,neurodegenerative disease,amyotrophic lateral sclerosis,mitochondria,superoxide dismutase,G93A transgenic mouse},
  language     = {eng},
  number       = {1},
  pages        = {128--137},
  publisher    = {American Association of Neurosurgeons},
  series       = {Journal of Neurosurgery},
  title        = {Life span extension and reduced neuronal death after weekly intraventricular cyclosporin injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis},
  volume       = {101},
  year         = {2004},
}