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 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 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 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.
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: Veronika M
authors.initials: VM
authors.lastname: Stein
authors.forename: Alexandra
authors.initials: A
authors.lastname: Crooks
authors.forename: Wenge
authors.initials: W
authors.lastname: Ding
authors.forename: Maria
authors.initials: M
authors.lastname: Prociuk
authors.forename: Patricia
authors.initials: P
authors.lastname: O'Donnell
authors.forename: Caroline
authors.initials: C
authors.lastname: Bryan
authors.forename: Tracey
authors.initials: T
authors.lastname: Sikora
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
authors.forename: Charles H
authors.initials: CH
authors.lastname: Vite
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D019540:Area Under Curve; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D016022:Case-Control Studies; D002371:Cat Diseases; D002415:Cats; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000097:blood; D005500:Follow-Up Studies; D020143:Gangliosidoses, GM2 / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000235:genetics / Q000662:veterinary; D010587:Phagocytosis / Q000187:drug effects; D010641:Phenotype; D011180:Postmortem Changes; D011689:Purkinje Cells / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D013110:Sphingosine / Q000378:metabolism; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D013109:Sphingomyelins; D017485:1-Deoxynojirimycin; D002784:Cholesterol; C059896:miglustat; D013110:Sphingosine