Therapeutics

Allopregnanolone

Overview

Name: Allopregnanolone
Synonyms: 3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)

Background

Allopregnanolone is a neurosteroid metabolite of progesterone. It is an allosteric modulator of inhibitory γ-aminobutyric acid (GABA-A) receptors on neural stem cells and other cell types in the brain (Luchetti et al., 2011). Allopregnanolone levels have been reported to be reduced in the temporal cortices of people with Alzheimer's disease (Naylor et al., 2010).

In transgenic Alzheimer's mouse models, allopregnanolone has been reported to increase neurogenesis, reduce amyloid deposition, and improve performance of learning and memory tests (e.g. Wang et al., 2010; Chen et al., 2011; Zhang et al., 2015). In mouse models of the lipid storage disease Niemann-Pick Type C, restoring low allopregnanolone levels lengthened survival. This neuroprotective effect is thought to be mediated by the pregnane X steroid receptor (Sep 2006 news).

The rationale behind evaluating allopregnanolone in Alzheimer's disease is that a combined regenerative and neuroprotective effect will counteract the ongoing neuronal cell loss in this neurodegenerative disease (Irwin et al., 2014). However, other studies have reported that allopregnanolone can impair learning function in two different AD mouse strains (e.g. Bengtsson et al., 2013).

Findings

In August 2014, an NIH-funded, Phase 1 study began comparing 2, 4, and 6 mg of allopregnanolone to placebo, all infused once a week for three months. Conducted at the University of Southern California, the study is enrolling 24 men and women with a clinical diagnosis of MCI due to AD or mild AD. Primary outcome measures include various safety parameters including brain MRI; secondary outcomes are pharmacokinetics, cognitive batteries, and structural and functional MRI. The trial is set to run until summer 2017. Both drug and placebo are being manufactured at the University of California, Davis (see Dec 2014 conference news, Aug 2013 news).

Allopregnanolone is also being evaluated in traumatic brain injury and other conditions. For all trials of allopregnanolone, see clinicaltrials.gov.

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References

News Citations

  1. Just for Her? Study of Women’s Biology Offers New Therapeutic Angle
  2. Clinical Trials Roundup: Broadening the Lines of Attack
  3. Cholesterol Metabolites Protect Neurons in Niemann-Pick C Disease

Paper Citations

  1. Luchetti S, Huitinga I, Swaab DF. Neurosteroid and GABA-A receptor alterations in Alzheimer's disease, Parkinson's disease and multiple sclerosis. Neuroscience. 2011 Sep 15;191:6-21. PubMed.
  2. Naylor JC, Kilts JD, Hulette CM, Steffens DC, Blazer DG, Ervin JF, Strauss JL, Allen TB, Massing MW, Payne VM, Youssef NA, Shampine LJ, Marx CE. Allopregnanolone levels are reduced in temporal cortex in patients with Alzheimer's disease compared to cognitively intact control subjects. Biochim Biophys Acta. 2010 Aug;1801(8):951-9. PubMed.
  3. Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung EJ, Thompson RF, Brinton RD. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6498-503. Epub 2010 Mar 15 PubMed.
  4. Chen S, Wang JM, Irwin RW, Yao J, Liu L, Brinton RD. Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer's disease. PLoS One. 2011;6(8):e24293. PubMed.
  5. Zhang P, Xie MQ, Ding YQ, Liao M, Qi SS, Chen SX, Gu QQ, Zhou P, Sun CY. Allopregnanolone enhances the neurogenesis of midbrain dopaminergic neurons in APPswe/PSEN1 mice. Neuroscience. 2015 Apr 2;290:214-26. Epub 2015 Jan 28 PubMed.
  6. Irwin RW, Solinsky CM, Brinton RD. Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders. Front Cell Neurosci. 2014;8:203. Epub 2014 Jul 30 PubMed.
  7. Bengtsson SK, Johansson M, Backstrom T, Nitsch RM, Wang M. Brief but Chronic Increase in Allopregnanolone Cause Accelerated AD Pathology Differently in Two Mouse Models. Curr Alzheimer Res. 2013 Jan 1;10(1):38-47. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Wang JM. Allopregnanolone and neurogenesis in the nigrostriatal tract. Front Cell Neurosci. 2014;8:224. Epub 2014 Aug 12 PubMed.
  2. Schumacher M, Mattern C, Ghoumari A, Oudinet JP, Liere P, Labombarda F, Sitruk-Ware R, De Nicola AF, Guennoun R. Revisiting the roles of progesterone and allopregnanolone in the nervous system: resurgence of the progesterone receptors. Prog Neurobiol. 2014 Feb;113:6-39. Epub 2013 Oct 27 PubMed.
  3. Irwin RW, Brinton RD. Allopregnanolone as regenerative therapeutic for Alzheimer's disease: Translational development and clinical promise. Prog Neurobiol. 2013 Sep 14; PubMed.
  4. Sun C, Ou X, Farley JM, Stockmeier C, Bigler S, Brinton RD, Wang JM. Allopregnanolone Increases the Number of Dopaminergic Neurons in Substantia Nigra of Triple Transgenic Mouse Model of Alzheimer's Disease. Curr Alzheimer Res. 2012 Jan 23; PubMed.
  5. Singh C, Liu L, Wang JM, Irwin RW, Yao J, Chen S, Henry S, Thompson RF, Brinton RD. Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice. Neurobiol Aging. 2011 Jul 29; PubMed.
  6. Luchetti S, Bossers K, Van de Bilt S, Agrapart V, Morales RR, Frajese GV, Swaab DF. Neurosteroid biosynthetic pathways changes in prefrontal cortex in Alzheimer's disease. Neurobiol Aging. 2011 Nov;32(11):1964-76. PubMed.