Cyclodextrin alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable blood-brain barrier permeability

J Inherit Metab Dis. 2013 May;36(3):491-8. doi: 10.1007/s10545-012-9583-x. Epub 2013 Feb 15.


Niemann-Pick type C disease is an inherited autosomal recessive neurodegenerative disorder characterised by the accumulation of unesterified cholesterol and sphingolipids within the endosomal/lysosomal compartments. It has been observed that the administration of hydroxypropyl-β-cyclodextrin (HPBCD) delays onset of clinical symptoms and reduces accumulation of cholesterol and gangliosides within neuronal cells. It was assumed that HPBCD exerts its action by readily entering the CNS and directly interacting with neurones and other brain cells to facilitate removal of stored cholesterol from the late endosomal/lysosomal compartment. Here, we present evidence that refutes this hypothesis. We use two well established techniques for accurately measuring brain uptake of solutes from blood and show that there is no significant crossing of HPBCD into the brain. The two techniques are brain in situ perfusion and intraperitoneal injection followed by multi-time-point regression analysis. Neither study demonstrates significant, time-dependent uptake of HPBCD in either adult or neonatal mice. However, the volume of distribution available to HPBCD (0.113 ± 0.010 ml/g) exceeds the accepted values for plasma and vascular volume of the brain. In fact, it is nearly three times larger than that for sucrose (0.039 ± 0.006 ml/g). We propose that this indicates cell surface binding of HPBCD to the endothelium of the cerebral vasculature and may provide a mechanism for the mobilisation and clearance of cholesterol from the CNS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Capillary Permeability / drug effects
  • Cholesterol / metabolism*
  • Drug Evaluation, Preclinical
  • Injections, Intraperitoneal
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Neurons / pathology
  • Niemann-Pick Diseases / drug therapy*
  • Niemann-Pick Diseases / genetics
  • Niemann-Pick Diseases / metabolism
  • Niemann-Pick Diseases / pathology
  • Perfusion
  • Proteins / genetics
  • Proteins / metabolism
  • beta-Cyclodextrins / administration & dosage
  • beta-Cyclodextrins / therapeutic use*


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