Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 71, Issue 5, Pages 434-448Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e31825414a6
Keywords
Animal model; Cholesterol; Feline model; Glucosylceramide synthase; Glycosphingolipid; Miglustat; Niemann-Pick
Categories
Funding
- Ara Parseghian Medical Research Foundation
- Dana's Angels Research Trust
- National Institutes of Health [NS053677]
- German Research Foundation [DFG-STE 1069/2-1]
- [NCRR02512]
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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 of human NPC disease received daily miglustat orally beginning at 3 weeks of age. The plasma half-life of miglustat was 6.6 +/- 1.1 hours, with a t(max), C-max, and area under the plasma concentration-time curve of 1.7 +/- 0.6 hours, 20.3 +/- 4.6 mu g/mL, and 104.1 +/- 16.6 mu g 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 of treated 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.
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