Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann‐Pick C mice

Ahmad, Iram; Lope–Piedrafita, Silvia; Bi, Xiaoning; Hicks, Chad; Yao, Yueqin; Yu, Clara; Chaitkin, Elizabeth; Howison, Christine M.; Weberg, Lyndon; Trouard, Theodore P.; Erickson, Robert P.

doi:10.1002/jnr.20685

Cited by 77 publications

(55 citation statements)

References 49 publications

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“…Our studies have now been repeated by other laboratories, which have demonstrated similar effects of allopregnanolone treatment on their colonies of NP-C mice (Ahmad, et al, 2005,Langmade, et al, 2006.…”

Section: Treatment Of Np-c Mice With Allopregnanolonesupporting

confidence: 58%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3ß HSD, as well as those that expressed 3α HSD and 5α reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of lifespan, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA A receptors may play a role. We treated NP-C mice with a synthetic GABA A neurosteroid, ganaxolone (3α-hydroxy-3β-methyl-5α -pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA A receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.

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Section: Treatment Of Np-c Mice With Allopregnanolonesupporting

confidence: 58%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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“…While administered in young mice (7 day-old Npc1 −/− mice), significant health improvements were observed including delayed degeneration and the life expectation of the animals was almost doubled [58][59][60]. Liu and colleagues (2009 [61]) reproduced equal observations when HPβCD alone was injected in 7-day-old Npc1 −/− mice.…”

Section: Niemann-pick Type C (Npc)mentioning

confidence: 99%

Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases

et al. 2016

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Cardiovascular diseases, like atherosclerosis, and neurodegenerative diseases affecting the central nervous system (CNS) are closely linked to alterations of cholesterol metabolism. Therefore, innovative pharmacological approaches aiming at counteracting cholesterol imbalance display promising therapeutic potential. However, these approaches need to take into account the existence of biological barriers such as intestinal and blood-brain barriers which participate in the organ homeostasis and are major defense systems against xenobiotics. Interest in cyclodextrins (CDs) as medicinal agents has increased continuously based on their ability to actively extract lipids from cell membranes and to provide suitable carrier system for drug delivery. Many novel CD derivatives are constantly generated with the objective to improve CD bioavailability, biocompatibility and therapeutic outcomes. Newly designed drug formulation complexes incorporating CDs as drug carriers have demonstrated better efficiency in treating cardiovascular and neurodegenerative diseases. CD-based therapies as cholesterol-sequestrating agent have recently demonstrated promising advances with KLEPTOSE ® CRYSMEB in atherosclerosis as well as with the 2-hydroxypropyl-β-cyclodextrin (HPβCD) in clinical trials for Niemann-Pick type C disease. Based on this success, many investigations evaluating the therapeutical beneficial of CDs in Alzheimer's, Parkinson's and Huntington's diseases are currently on-going.

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“…Ϫ / Ϫ mice ( 121,122 ). The ALLO was delivered via hydroxypropyl-␤ -cyclodextrin (HPBCD), but treatment with HPBCD alone had no effect in these studies.…”

Section: Mln64 and Menthomentioning

confidence: 99%

Early steps in steroidogenesis: intracellular cholesterol trafficking

Miller

Bose

2011

Journal of Lipid Research

444

398

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Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann‐Pick C mice

Cited by 77 publications

References 49 publications

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases

Early steps in steroidogenesis: intracellular cholesterol trafficking

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