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 GABA(A) 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 GABA(A) 
receptor agonist. ent-ALLO provided identical functional and survival benefits 
as natural ALLO in npc1(-/-) mice, strongly supporting a GABA(A) 
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.