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 journalArticle

116 Citations (Scopus)

Abstract

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
Volume103
Issue number37
DOIs
StatePublished - Sep 12 2006

Fingerprint

Niemann-Pick Diseases
Pregnanolone
Type C Niemann-Pick Disease
Purkinje Cells
GABA-A Receptors
Neuroprotection
pregnane X receptor
GABA-A Receptor Agonists
Ligands
Stereoisomerism
Microglia
Neurodegenerative Diseases
Cerebellum
Neurotransmitter Agents
Disease Progression
Therapeutics

Keywords

  • Allopregnanolone
  • Cholesterol
  • Neurodegeneration
  • Neurosteroid

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Pregnane X receptor (PXR) activation : A mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. / Langmade, S. Joshua; Gale, Sarah E.; Frolov, Andrey; Mohri, Ikuko; Suzuki, Kinuko; Mellon, Synthia H.; Walkley, Steven U.; Covey, Douglas F.; Schaffer, Jean E.; Ory, Daniel S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 37, 12.09.2006, p. 13807-13812.

Research output: Contribution to journalArticle

Langmade, S. Joshua ; Gale, Sarah E. ; Frolov, Andrey ; Mohri, Ikuko ; Suzuki, Kinuko ; Mellon, Synthia H. ; Walkley, Steven U. ; Covey, Douglas F. ; Schaffer, Jean E. ; Ory, Daniel S. / Pregnane X receptor (PXR) activation : A mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 37. pp. 13807-13812.
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