Activation of the pregnane X steroid receptor (PXR) prevents neurodegeneration in a mouse model of the cholesterol metabolic disorder Niemann-Pick C disease, according to a new study from Daniel Ory and colleagues at Washington University School of Medicine in St. Louis. In a report out August 29 in the PNAS Early Edition, the researchers show that treating mice with cholesterol derivatives that activate PXR and turn on its target genes preserved Purkinje cells, prevented inflammation, and improved survival and motor function.

The investigators speculate that induction of detoxifying P450 enzymes by PXR might counteract the oxidative damage that occurs as cholesterol accumulates in neurons in the disease. The nuclear PXR is part of the cellular defense against toxic chemicals, and it binds several prescription drugs and also some endogenous steroids. When activated, it turns on several genes, including the cytochrome P450-3A. The human PXR is activated by commonly used drugs including rifampicin, phenytoin and hyperphorin (a constituent of St. John’s wort), which could speed trials of potential new treatments for the disease.

Niemann-Pick C disease is caused by a mutation in the Niemann-Pick C gene (npc), which results in accumulation of cholesterol in the CNS and eventual Purkinje cell death. An npc-/- mouse model shows abnormal neuronal lipid storage and progressive Purkinje neuron loss. There is also disruption of cholesterol transport between brain cells.

Due to these derangements in cholesterol metabolism, npc-/- mice have lower levels of the cholesterol-derived neurosteroids pregnenolone and allopregnenolone. They also fail to make sufficient amounts of the cholesterol metabolites 25- and 27-hydroxycholesterol, which themselves are important for proper regulation of cholesterol metabolism. Giving the animals replacement doses of either allopregnenolone (ALLO) or pregnenolone prolonged survival in the mouse model, according to previous work, but only if the compounds were given in the first few days of life. In the new study, first authors Joshua Langmade and Sara Gale confirmed this result, and further showed that early treatment with ALLO followed by later doses of the hydroxycholesterol mimic T0901317 together further delayed the onset of symptoms and prolonged survival in the mice. The regimen spared Purkinje cells and prevented the inflammatory response to cell death.

Looking into how the treatment actually worked, the researchers first checked out the GABAA receptor, which responds to steroids and has been suggested to mediate the effects of ALLO on Purkinje cell survival. But they quickly learned this was not the relevant pathway, as an enantiomeric form of ALLO that no longer bound GABAA showed full protective activity in the mice. Instead, the activity of both ALLO and T0901317 correlated with their ability to activate the murine PXR in vitro. Both compounds increased expression of the PXR target cytochrome P4503A13 enzyme in vivo in mouse cerebellum.—Pat McCaffrey


  1. The findings of Langmade, Gale, and colleagues, that allopregnanolone delayed progression of pathology and promoted survival, potentially through a PXR receptor-mediated mechanism, has exciting mechanistic and therapeutic implications. Mechanistically, allopregnanolone activation of the PXR receptor, leading to an increase in the cytochrome P450 enzyme CYP3A13, suggests a novel mechanism of allopregnanolone neuroprotection that brings the benefits of "liver" detox to the brain. Therapeutically, activating “liver-type” detoxification in brain may be a broad-spectrum strategy for promoting neurological health and defense against neurodegenerative insults.

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Primary Papers

  1. . Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc Natl Acad Sci U S A. 2006 Aug 29; PubMed.