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

Charles C. Pontikis, Cristin D. Davidson, Steven U. Walkley, Frances M. Platt, David J. Begley

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)491-498
Number of pages8
JournalJournal of Inherited Metabolic Disease
Volume36
Issue number3
DOIs
StatePublished - May 2013

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Niemann-Pick Diseases
Cyclodextrins
Blood-Brain Barrier
Permeability
Cholesterol
Brain
Type C Niemann-Pick Disease
Sphingolipids
Plasma Volume
Gangliosides
Intraperitoneal Injections
Neurodegenerative Diseases
Endothelium
Blood Vessels
Sucrose
Perfusion
Regression Analysis
Neurons

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Cyclodextrin alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable blood-brain barrier permeability. / Pontikis, Charles C.; Davidson, Cristin D.; Walkley, Steven U.; Platt, Frances M.; Begley, David J.

In: Journal of Inherited Metabolic Disease, Vol. 36, No. 3, 05.2013, p. 491-498.

Research output: Contribution to journalArticle

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