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

  title={Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann‐Pick C mice},
  author={Iram Ahmad and Silvia Lope-Piedrafita and Xiaoning Bi and Chad Hicks and Yueqin Yao and Clara Yu and Elizabeth Chaitkin and Christine M. Howison and Lyndon Weberg and Theodore P. Trouard and Robert P. Erickson},
  journal={Journal of Neuroscience Research},
Niemann‐Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1–/– mice). We confirmed previous results showing that a single injection of 250 μg of allopregnanolone on… 

MRI detects therapeutic effects in weanling Niemann‐Pick type C mice

Beneficial effects of treatment with allopregnanolone and/or 2 hydroxypropyl‐beta‐cyclodextrin was also detectable at this age by FA, which correlated with increased myelination as seen by histology, which is the earliest detection of a therapeutic effect in Npc1–/– mice.

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

It is shown 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, suggesting that treatment with pregnane X receptor ligands may be useful clinically in delaying the progressive neurodegeneration in human NPC disease.

Gender-Specific Effects of Two Treatment Strategies in a Mouse Model of Niemann-Pick Disease Type C1

Comparing the therapeutic effects of the COMBI therapy with that of MIGLU or HPßCD alone on body and brain weight and the behavior of NPC1−/− mice in a larger cohort is designed, with special reference to gender differences.

Astrocyte‐only Npc1 reduces neuronal cholesterol and triples life span of Npc1–/– mice

It is concluded that neurodegeneration of Npc1–/– mice is greatly affected by the loss of fibrillary astrocyte function.

Neuroregenerative Mechanisms of Allopregnanolone in Alzheimer’s Disease

To the knowledge, APα is the only small molecule that both promotes neural progenitor regeneration in brain and simultaneously reduces AD pathology burden.

Allopregnanolone Promotes Regeneration and Reduces β-Amyloid Burden in a Preclinical Model of Alzheimer's Disease

The efficacy of APα to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD) pathology in the 3xTgAD male mouse model and the optimal treatment regimen to achieve efficacy as a disease modifying therapeutic are determined.

Therapeutic potential of cyclodextrins in the treatment of Niemann–Pick type C disease

The pathophysiology of NPC disease is explored and the use of 2HPBCD as a possible therapeutic modality is explored.



Niemann–Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone

It is shown that NP-C mouse brain contains substantially less neurosteroid than wild-type brain and has an age-related decrease in the ability to synthesize 5α-dihydroprogesterone and allopregnanolone, and neurosteroids made in the brain may be useful in ameliorating progression of the disease.

Studies on neuronal death in the mouse model of Niemann‐Pick C disease

Results suggest that Purkinje cell loss in npc1−/− mice does not proceed by an apoptotic pathway that can be inhibited by Bcl‐2 or minocycline.

Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene.

Transgenic mice made in which the wild-type NPC1 protein is expressed primarily in the CNS of transgenic animals demonstrated that overexpression of NPC1 is not harmful and allowing possibilities for genetic therapy interventions that utilize overeexpression.

Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease.

mdr1a deficiency corrects sterility in Niemann–Pick C1 protein deficient female mice

The results show that a mdr1a mutation is an in vivo suppressor of female sterility in npc1 deficient mice.

The murine Niemann-Pick type C lesion affects testosterone production.

It is concluded that a defect in testicular testosterone production in NPC male mice causes a pleiotropic deficiency in androgen-sensitive expression of proteins in various organs.

Cholesterol Accumulation in NPC1-Deficient Neurons Is Ganglioside Dependent

Allopregnanolone, a progesterone metabolite, enhances behavioral recovery and decreases neuronal loss after traumatic brain injury.

It is suggested that allopregnanolone may mediate the effects of progesterone in promoting cognitive and morphological recovery from TBI through, among others, its direct or indirect effects on GABA-modulated neurons in the MDN and the NBM.