Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann-Pick C disease

S. Joshua Langmade, Sarah E. Gale, Andrey Frolov, Ikuko Mohri, Kinuko Suzuki, Synthia H. Mellon, Steven U. Walkley, Douglas F. Covey, Jean E. Schaffer, Daniel S. Ory

Research output: Contribution to journalArticlepeer-review

138 Scopus citations


Niemann-Pick type C1 (NPC1) disease is a fatal neurodegenerative disease characterized by neuronal lipid storage and progressive Purkinje cell loss in the cerebellum. We investigated whether therapeutic approaches to bypass the cholesterol trafficking defect in NPC1 disease might delay disease progression in the npc1-/- mouse model. We show that the neurosteroid allopregnanolone (ALLO) and T0901317, a synthetic oxysterol ligand, act in concert to delay onset of neurological symptoms and prolong the lifespan of npc1-/- mice. ALLO and T0901317 therapy preserved Purkinje cells, suppressed cerebellar expression of microglial-associated genes and inflammatory mediators, and reduced infiltration of activated microglia in the cerebellar tissue. To establish whether the mechanism of neuroprotection in npc1 -/- mice involves GABAA receptor activation, we compared treatment of natural ALLO and ent-ALLO, a stereoisomer that has identical physical properties of natural ALLO but is not a GABAA receptor agonist. ent-ALLO provided identical functional and survival benefits as natural ALLO in npc1 -/- mice, strongly supporting a GABAA receptor-independent mechanism for ALLO action. On the other hand, the efficacy of ALLO, ent-ALLO, and T0901317 therapy correlated with the ability of these compounds to activate pregnane X receptor-dependent pathways in vivo. These findings suggest that treatment with pregnane X receptor ligands may be useful clinically in delaying the progressive neurodegeneration in human NPC disease.

Original languageEnglish (US)
Pages (from-to)13807-13812
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 12 2006


  • Allopregnanolone
  • Cholesterol
  • Neurodegeneration
  • Neurosteroid

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann-Pick C disease'. Together they form a unique fingerprint.

Cite this