U18666A inhibits intracellular cholesterol transport and neurotransmitter release in human neuroblastoma cells

Neurochem Res. 1999 Jan;24(1):69-77. doi: 10.1023/a:1020932130753.


To determine if neurochemical function might be impaired in cell models with altered cholesterol balance, we studied the effects of U18666A (3-beta-[(2-diethyl-amino)ethoxy]androst-5-en-17-one) on intracellular cholesterol metabolism in three human neuroblastoma cell lines (SK-N-SH, SK-N-MC, and SH-SY5Y). U18666A (< or =0.2 microg/ml) completely inhibited low density lipoprotein (LDL)-stimulated cholesterol esterification in SK-N-SH cells, while cholesterol esterification stimulated by 25-hydroxycholesterol or bacterial sphingomyelinase was unaffected or partially inhibited, respectively. U18666A also blocked LDL-stimulated downregulation of LDL receptor and caused lysosomal accumulation of cholesterol as measured by filipin staining. U18666A treatment for 18 h resulted in 70% inhibition of K+-evoked norepinephrine release in phorbol ester-differentiated SH-SY5Y cells, while release stimulated by the calcium ionophore A23187 was only slightly affected. These results suggest that U 18666A may preferentially block a voltage-regulated Ca2+ channel involved in norepinephrine release and that alterations in neurotransmitter secretion might be a feature of disorders such as Niemann-Pick Type C, in which intracellular cholesterol transport and distribution are impaired.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstenes / pharmacology*
  • Anticholesteremic Agents / pharmacology*
  • Biological Transport / drug effects
  • Calcimycin / pharmacology
  • Calcium Channels / physiology
  • Cholesterol / metabolism*
  • Culture Media
  • Down-Regulation
  • Humans
  • Hydroxycholesterols / pharmacology
  • Kinetics
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Neuroblastoma / metabolism*
  • Norepinephrine / metabolism*
  • Potassium / pharmacology
  • Receptors, LDL / drug effects
  • Receptors, LDL / metabolism*
  • Sphingomyelin Phosphodiesterase / pharmacology
  • Staphylococcus aureus / enzymology
  • Tumor Cells, Cultured


  • Androstenes
  • Anticholesteremic Agents
  • Calcium Channels
  • Culture Media
  • Hydroxycholesterols
  • Receptors, LDL
  • 3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one
  • Calcimycin
  • 25-hydroxycholesterol
  • Cholesterol
  • Sphingomyelin Phosphodiesterase
  • Potassium
  • Norepinephrine