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 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.
Biswas
Sangita
S
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Biesiada
Homigol
H
Williams
Todd D
TD
LeVine
Steven M
SM
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003523:Cycloserine / Q000737:chemistry / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D007965:Leukodystrophy, Globoid Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D007652:Oxo-Acid-Lyases / Q000235:genetics / Q000378:metabolism; D011609:Psychosine / Q000378:metabolism
D004791:Enzyme Inhibitors; D011609:Psychosine; D003523:Cycloserine; C021473:3-ketodihydrosphingosine synthetase; D007652:Oxo-Acid-Lyases