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

Abstract

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/6xCAST/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 approximately 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.

• Authors: Sangita Biswas, Homigol Biesiada, Todd D Williams, Steven M LeVine
• Journal: Neuroscience letters (Neurosci Lett) Vol. 347 Issue 1 Pg. 33-6 (Aug 14 2003) ISSN: 0304-3940 [Print] Ireland
• PMID: 12865135 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Psychosine
• Cycloserine
• 3-ketodihydrosphingosine synthetase
• Oxo-Acid-Lyases

Topics

• Animals
• Body Weight (drug effects)
• Cycloserine (chemistry, therapeutic use)
• Enzyme Inhibitors (chemistry, therapeutic use)
• Leukodystrophy, Globoid Cell (drug therapy, genetics, metabolism)
• Longevity (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Neurologic Mutants
• Oxo-Acid-Lyases (genetics, metabolism)
• Psychosine (metabolism)