Miglustat improves purkinje cell survival and alters microglial phenotype in feline niemann-pick disease type C

Veronika M. Stein, Alexandra Crooks, Wenge Ding, Maria Prociuk, Patricia O'Donnell, Caroline Bryan, Tracey Sikora, Jasper Dingemanse, Marie T. Vanier, Steven U. Walkley, Charles H. Vite

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Abstract

Niemann-Pick disease type C (NPC disease) is an incurable cellular lipid-trafficking disorder characterized by neurodegeneration and intralysosomal accumulation of cholesterol and glycosphingolipids. Treatment with miglustat, a small imino sugar that reversibly inhibits glucosylceramide synthase, which is necessary for glycosphingolipid synthesis, has been shown to benefit patients with NPC disease. The mechanism(s) and extent of brain cellular changes underlying this benefit are not understood. To investigate the basis of the efficacy of miglustat, cats with disease homologous to the juvenile-onset form ofhuman NPC disease received daily miglustat orally beginning at 3weeks of age. The plasma half-life of miglustat was 6.6 ± 1.1 hours, with a tmax, Cmax, and area under the plasma concentration-time curve of 1.7 ± 0.6 hours, 20.3 ± 4.6 μg/mL, and 104.1 ± 16.6 μg hours/mL, respectively. Miglustat delayed the onset of neurological signs and increased the lifespan of treated cats and was associated with decreased GM2 ganglioside accumulation in the cerebellum and improved Purkinje cell survival. Ex vivo examination of microglia from the brains oftreated cats revealed normalization of CD1c and class II major histocompatibility complex expression, as well as generation of reactive oxygen species. Together, these results suggest that prolonged Purkinje cell survival, reduced glycosphingolipid accumulation, and/or the modulation of microglial immunophenotype and function contribute to miglustat-induced neurological improvement in treated cats.

Original languageEnglish (US)
Pages (from-to)434-448
Number of pages15
JournalJournal of Neuropathology and Experimental Neurology
Volume71
Issue number5
DOIs
Publication statusPublished - May 1 2012

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Keywords

  • Animal model
  • Cholesterol
  • Feline model
  • Glucosylceramide synthase
  • Glycosphingolipid
  • Miglustat
  • Niemann-Pick

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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