Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease

Life Sci. 2001 Nov 30;70(2):131-42. doi: 10.1016/s0024-3205(01)01384-4.


Niemann-Pick type C (NPC) is a neurodegenerative disorder characterized by greatly altered somatic cholesterol metabolism. The NPC1 gene has recently been cloned and shown to have sequence homology to other sterol-sensing proteins. We have used a mouse model with a disrupted npc1 gene to study the effects of the cholesterol-mobilizing compound, 2-hydroxypropyl-beta-cyclodextrins (HPBCD), on the clinical course of this disorder. Treatment with two HPBCDs, with varying levels of 2-hydroxypropyl substitution, had effects in delaying neurological symptoms and in decreasing liver cholesterol storage while a third HPBCD was without effect. The ameliorating effect was not improved by longer exposure times (commencement of exposure in utero), however, it is not known if there is transplacental transfer of HPBCDs. The combination of HPBCD with probucol or nifedipine (which have previously been shown to lower liver cholesterol in this animal model) markedly decreased liver storage of unesterified cholesterol without altering the depressed levels of esterified cholesterol. The slight effects of the HPBCDs on neurological symptoms may be partially due to their apparent non-permeation of the blood-brain barrier (BBB). This non-permeation was assayed with radioactive tracers and was also present in the mdr1a knockout mice which have greatly increased BBB permeability for many drugs. Intrathecal delivery of HPBCD by an Alzet osmotic minipump did not improve its efficacy in ameliorating neurological symptoms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Animals
  • Anticholesteremic Agents / administration & dosage
  • Anticholesteremic Agents / pharmacokinetics
  • Anticholesteremic Agents / therapeutic use*
  • Ataxia / drug therapy
  • Ataxia / physiopathology
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / physiology
  • Brain / drug effects
  • Brain / metabolism
  • Cholesterol / analysis
  • Cyclodextrins / administration & dosage
  • Cyclodextrins / pharmacokinetics
  • Cyclodextrins / therapeutic use*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Female
  • Injections, Intraperitoneal
  • Injections, Spinal
  • Intracellular Signaling Peptides and Proteins
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Niemann-Pick Diseases / drug therapy*
  • Niemann-Pick Diseases / genetics
  • Niemann-Pick Diseases / physiopathology
  • Nifedipine / therapeutic use
  • Probucol / therapeutic use
  • Proteins / genetics
  • Tremor / drug therapy
  • Tremor / physiopathology
  • beta-Cyclodextrins*


  • Anticholesteremic Agents
  • Cyclodextrins
  • Intracellular Signaling Peptides and Proteins
  • Npc1 protein, mouse
  • Proteins
  • beta-Cyclodextrins
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Cholesterol
  • Nifedipine
  • Probucol