Substrate reduction intervention by l-cycloserine in twitcher mice (globoid cell leukodystrophy) on a B6;CAST/Ei background

Globoid cell leukodystrophy (GCL) is usually a fatal demyelinating disease caused by mutations in galactosylceramidase, which normally recycles galactosylceramide, a predominant glycolipid of myelin, and psychosine. The initial pathology is thought to be due to the accumulation of psychosine in myel...

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Bibliographic Details
Published in:Neuroscience letters 2003-08, Vol.347 (1), p.33-36
Main Authors: Biswas, Sangita, Biesiada, Homigol, Williams, Todd D., LeVine, Steven M.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Body Weight - drug effects
Cycloserine - chemistry
Cycloserine - therapeutic use
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Demyelination
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - therapeutic use
Galactosylceramide
Krabbe disease
l-Cycloserine
Leukodystrophy, Globoid Cell - drug therapy
Leukodystrophy, Globoid Cell - genetics
Leukodystrophy, Globoid Cell - metabolism
Longevity - drug effects
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Neurologic Mutants
Neurology
Oxo-Acid-Lyases - genetics
Oxo-Acid-Lyases - metabolism
Psychosine
Psychosine - metabolism
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Summary:Globoid cell leukodystrophy (GCL) is usually a fatal demyelinating disease caused by mutations in galactosylceramidase, which normally recycles galactosylceramide, a predominant glycolipid of myelin, and psychosine. The initial pathology is thought to be due to the accumulation of psychosine in myelin-forming cells leading to their death. In this study, substrate reduction therapy using l-cycloserine, an inhibitor of 3-ketodihydrosphingosine synthase, was examined in twitcher mice on a C57BL/6×CAST/Ei (B6;CAST/Ei) background, which mimics a late onset variant of GCL. A graded dose regimen of l-cycloserine initiated before the onset of symptoms increased the lifespan by ∼45% and delayed the onset of weight loss while the administration of l-cycloserine beginning after the onset of symptoms had no effect. Despite the pronounced effect for the early treatment regimen, B6;CAST/Ei twitcher mice still displayed a progressive disease leading to an early death.
ISSN:0304-3940
1872-7972
DOI:10.1016/S0304-3940(03)00633-5