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

Research output: Contribution to journalArticle

49 Citations (Scopus)

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
StatePublished - May 2012

Fingerprint

Type C Niemann-Pick Disease
Purkinje Cells
Felidae
Cell Survival
Phenotype
Glycosphingolipids
Cats
ceramide glucosyltransferase
Imino Sugars
G(M2) Ganglioside
Cat Diseases
Brain
Microglia
Major Histocompatibility Complex
Cerebellum
Half-Life
miglustat
Reactive Oxygen Species
Cholesterol
Lipids

Keywords

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

ASJC Scopus subject areas

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

Cite this

Miglustat improves purkinje cell survival and alters microglial phenotype in feline niemann-pick disease type C. / Stein, Veronika M.; Crooks, Alexandra; Ding, Wenge; Prociuk, Maria; O'Donnell, Patricia; Bryan, Caroline; Sikora, Tracey; Dingemanse, Jasper; Vanier, Marie T.; Walkley, Steven U.; Vite, Charles H.

In: Journal of Neuropathology and Experimental Neurology, Vol. 71, No. 5, 05.2012, p. 434-448.

Research output: Contribution to journalArticle

Stein, VM, Crooks, A, Ding, W, Prociuk, M, O'Donnell, P, Bryan, C, Sikora, T, Dingemanse, J, Vanier, MT, Walkley, SU & Vite, CH 2012, 'Miglustat improves purkinje cell survival and alters microglial phenotype in feline niemann-pick disease type C', Journal of Neuropathology and Experimental Neurology, vol. 71, no. 5, pp. 434-448. https://doi.org/10.1097/NEN.0b013e31825414a6
Stein, Veronika M. ; Crooks, Alexandra ; Ding, Wenge ; Prociuk, Maria ; O'Donnell, Patricia ; Bryan, Caroline ; Sikora, Tracey ; Dingemanse, Jasper ; Vanier, Marie T. ; Walkley, Steven U. ; Vite, Charles H. / Miglustat improves purkinje cell survival and alters microglial phenotype in feline niemann-pick disease type C. In: Journal of Neuropathology and Experimental Neurology. 2012 ; Vol. 71, No. 5. pp. 434-448.
@article{d0208a1bd8a246da95aebb9fa558a91e,
title = "Miglustat improves purkinje cell survival and alters microglial phenotype in feline niemann-pick disease type C",
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.",
keywords = "Animal model, Cholesterol, Feline model, Glucosylceramide synthase, Glycosphingolipid, Miglustat, Niemann-Pick",
author = "Stein, {Veronika M.} and Alexandra Crooks and Wenge Ding and Maria Prociuk and Patricia O'Donnell and Caroline Bryan and Tracey Sikora and Jasper Dingemanse and Vanier, {Marie T.} and Walkley, {Steven U.} and Vite, {Charles H.}",
year = "2012",
month = "5",
doi = "10.1097/NEN.0b013e31825414a6",
language = "English (US)",
volume = "71",
pages = "434--448",
journal = "American Journal of Psychotherapy",
issn = "0002-9564",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Miglustat improves purkinje cell survival and alters microglial phenotype in feline niemann-pick disease type C

AU - Stein, Veronika M.

AU - Crooks, Alexandra

AU - Ding, Wenge

AU - Prociuk, Maria

AU - O'Donnell, Patricia

AU - Bryan, Caroline

AU - Sikora, Tracey

AU - Dingemanse, Jasper

AU - Vanier, Marie T.

AU - Walkley, Steven U.

AU - Vite, Charles H.

PY - 2012/5

Y1 - 2012/5

N2 - 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.

AB - 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.

KW - Animal model

KW - Cholesterol

KW - Feline model

KW - Glucosylceramide synthase

KW - Glycosphingolipid

KW - Miglustat

KW - Niemann-Pick

UR - http://www.scopus.com/inward/record.url?scp=84860224053&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860224053&partnerID=8YFLogxK

U2 - 10.1097/NEN.0b013e31825414a6

DO - 10.1097/NEN.0b013e31825414a6

M3 - Article

VL - 71

SP - 434

EP - 448

JO - American Journal of Psychotherapy

JF - American Journal of Psychotherapy

SN - 0002-9564

IS - 5

ER -