Synonyms: brexanolone, 3α-hydroxy-5α-pregnan-20-one, 3α,5α-tetrahydroprogesterone
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)
Status in Select Countries: Approved for postpartum depression
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 on 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 drug also has been proposed to promote neuron and oligodendrocyte maturation and improve mitochondrial function in AD mice (Chen et al., 2020; Wang et al., 2020). In mouse models of the lipid storage disease Niemann-Pick Type C, restoring low allopregnanolone levels lengthened survival, a neuroprotective effect thought to be mediated by the pregnane X steroid receptor (Sep 2006 news).
The rationale behind evaluating allopregnanolone in Alzheimer's is that a combined regenerative and neuroprotective effect may counteract 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). Newer data indicate that continuous elevation of allopregnanolone in mice worsens amyloid load and learning, while intermittent dosing has opposite, beneficial effects (Bengtsson et al., 2020).
From August 2014 to February 2018, an NIH-funded, Phase 1 study compared 2, 4, and 6 up to 18 mg of allopregnanolone to placebo, all infused once a week for three months. Conducted at the University of Southern California, the study enrolled 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. Both drug and placebo were being manufactured at the University of California, Davis (see Dec 2014 conference news; Aug 2013 news).
According to trial results presented at the 2018 CTAD meeting, the 2, 4, and 6 mg doses produced no adverse events or amyloid-related imaging abnormalities on MRI, and clinical results remained in the normal range. The drug caused sleepiness at 10 mg in women and 6 mg in men. Treatment was associated with less atrophy of the left hippocampus compared to placebo, more so in APOE4 carriers. The 4 and 6 mg doses improved functional connectivity in some brain regions. Exploratory cognitive measures found high variability and no significant differences between drug and placebo groups (Nov 2018 conference news).
In October 2019, a Phase 1 dose-finding study at the University of Southern California began testing intramuscular injections of allopregnanolone in lieu of infusions. The is enrolling 12 people with MCI due to AD or mild AD to receive 4 to 18 mg of drug weekly for up to 4 weeks, with pharmacokinetic analysis to determine the equivalent dose to the 4 mg infusion. Participants will continue that dose for a total of 12 weeks. Endpoints are safety, pharmacokinetics, patient satisfaction, and feasibility. Other outcomes include MRI measures of brain volume, standard tests of cognition, daily function, sleep quality and physical activity. The trial will finish in October 2020.
According to investigators, a Phase 2 trial with 200 participants is underway (see Cable et al., 2020), but is not registered to date.
Allopregnanolone is also being evaluated in traumatic brain injury, as well as post-traumatic stress, depression and anxiety disorders. For all trials of allopregnanolone, see clinicaltrials.gov.
Last Updated: 21 Jul 2020
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- Cable J, Holtzman DM, Hyman BT, Tansey MG, Colonna M, Kellis M, Brinton RD, Albert M, Wellington CL, Sisodia SS, Tanzi RE. Alternatives to amyloid for Alzheimer's disease therapies-a symposium report. Ann N Y Acad Sci. 2020 May 29; PubMed.
- 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.
- 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.
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- 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.
- 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.
- Chen S, Wang T, Yao J, Brinton RD. Allopregnanolone Promotes Neuronal and Oligodendrocyte Differentiation In Vitro and In Vivo: Therapeutic Implication for Alzheimer's Disease. Neurotherapeutics. 2020 Jul 6; PubMed.
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- Bengtsson SK, Bäckström T, Brinton R, Irwin RW, Johansson M, Sjöstedt J, Wang MD. GABA-A receptor modulating steroids in acute and chronic stress; relevance for cognition and dementia?. Neurobiol Stress. 2020 May;12:100206. Epub 2019 Dec 20 PubMed.
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- 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.
- Irwin RW, Brinton RD. Allopregnanolone as regenerative therapeutic for Alzheimer's disease: Translational development and clinical promise. Prog Neurobiol. 2013 Sep 14; PubMed.
- 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.
- 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.
- 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.