Allopregnanolone: Regenerative Therapeutic to Restore Neurological Health

Overview

Journal Neurobiol Stress

Date 2022 Dec 19

PMID 36532370

Authors

Gerson D Hernandez

Roberta D Brinton

Affiliations

Soon will be listed here.

Abstract

Chronic stress has been proposed as a driver of altered brain structure and function, including the pathogenesis of neurodegenerative diseases and a driver of disease progression. A key outcome of stress in the brain is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicate failed resilience. Neuroendocrine homeostasis and stress response are mainly dependent upon the functioning of the hypothalamic-pituitary-adrenal axis. Neurosteroids will fluctuate depending on whether the stress is acute or chronic. Advancements in neurosteroid research have led to the identification of multiple targets for drug development, but the most promising innovative target may be neurogenesis, given its potential impact in neurodegenerative disorders like Alzheimer's disease. Allopregnanolone is an endogenous pregnane neurosteroid and a reduced metabolite of progesterone, which acts as a potent allosteric modulator and direct activator of the GABA-chloride channel complex. Perhaps the most intriguing finding related to the potential therapeutic effects of allopregnanolone is its potential to promote neuroregeneration.

Citing Articles

Functional Food Nutrients, Redox Resilience Signaling and Neurosteroids for Brain Health.

Scuto M, Majzunova M, Torcitto G, Antonuzzo S, Rampulla F, Di Fatta E Int J Mol Sci. 2024; 25(22).

PMID: 39596221 PMC: 11594618. DOI: 10.3390/ijms252212155.

Emerging Pro-neurogenic Therapeutic Strategies for Neurodegenerative Diseases: A Review of Pre-clinical and Clinical Research.

Vassal M, Martins F, Monteiro B, Tambaro S, Martinez-Murillo R, Rebelo S Mol Neurobiol. 2024; 62(1):46-76.

PMID: 38816676 PMC: 11711580. DOI: 10.1007/s12035-024-04246-w.

Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders.

Balan I, Boero G, Chery S, McFarland M, Lopez A, Morrow A Life (Basel). 2024; 14(5).

PMID: 38792602 PMC: 11122352. DOI: 10.3390/life14050582.

Simultaneous Determination of Selected Steroids with Neuroactive Effects in Human Serum by Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry.

Kaleta M, Oklestkova J, Klicova K, Kvasnica M, Konickova D, Mensikova K ACS Chem Neurosci. 2024; 15(10):1990-2005.

PMID: 38655788 PMC: 11099924. DOI: 10.1021/acschemneuro.3c00824.

Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism.

Wang T, Chen S, Mao Z, Shang Y, Brinton R Front Endocrinol (Lausanne). 2024; 14:1286931.

PMID: 38189047 PMC: 10771836. DOI: 10.3389/fendo.2023.1286931.

References

Mendelson W, Martin J, Perlis M, Wagner R, Majewska M, Paul S . Sleep induction by an adrenal steroid in the rat. Psychopharmacology (Berl). 1987; 93(2):226-9. DOI: 10.1007/BF00179939. View

Barbaccia M, Roscetti G, Trabucchi M, Mostallino M, Concas A, Purdy R . Time-dependent changes in rat brain neuroactive steroid concentrations and GABAA receptor function after acute stress. Neuroendocrinology. 1996; 63(2):166-72. DOI: 10.1159/000126953. View

Baulieu E, Robel P . Neurosteroids: a new brain function?. J Steroid Biochem Mol Biol. 1990; 37(3):395-403. DOI: 10.1016/0960-0760(90)90490-c. View

Osborne L, Betz J, Yenokyan G, Standeven L, Payne J . The Role of Allopregnanolone in Pregnancy in Predicting Postpartum Anxiety Symptoms. Front Psychol. 2019; 10:1033. PMC: 6646409. DOI: 10.3389/fpsyg.2019.01033. View

Anacker C, Hen R . Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood. Nat Rev Neurosci. 2017; 18(6):335-346. PMC: 6261347. DOI: 10.1038/nrn.2017.45. View

Paul S, Purdy R . Neuroactive steroids. FASEB J. 1992; 6(6):2311-22. View

Bali A, Jaggi A . Multifunctional aspects of allopregnanolone in stress and related disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2013; 48:64-78. DOI: 10.1016/j.pnpbp.2013.09.005. View

Schneider L, Hernandez G, Zhao L, Franke A, Chen Y, Pawluczyk S . Safety and feasibility of estrogen receptor-β targeted phytoSERM formulation for menopausal symptoms: phase 1b/2a randomized clinical trial. Menopause. 2019; 26(8):874-884. PMC: 6663614. DOI: 10.1097/GME.0000000000001325. View

Hernandez G, Solinsky C, Mack W, Kono N, Rodgers K, Wu C . Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial. Alzheimers Dement (N Y). 2020; 6(1):e12107. PMC: 7744018. DOI: 10.1002/trc2.12107. View

10.

McEwen B, Gianaros P . Stress- and allostasis-induced brain plasticity. Annu Rev Med. 2010; 62:431-45. PMC: 4251716. DOI: 10.1146/annurev-med-052209-100430. View

11.

Rasmusson A, Pinna G, Paliwal P, Weisman D, Gottschalk C, Charney D . Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol Psychiatry. 2006; 60(7):704-13. DOI: 10.1016/j.biopsych.2006.03.026. View

12.

Wang J, Singh C, Liu L, Irwin R, Chen S, Chung E . Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010; 107(14):6498-503. PMC: 2851948. DOI: 10.1073/pnas.1001422107. View

13.

Jurkowski M, Bettio L, Woo E, Patten A, Yau S, Gil-Mohapel J . Beyond the Hippocampus and the SVZ: Adult Neurogenesis Throughout the Brain. Front Cell Neurosci. 2020; 14:576444. PMC: 7550688. DOI: 10.3389/fncel.2020.576444. View

14.

Yassa M, Tugan Muftuler L, Stark C . Ultrahigh-resolution microstructural diffusion tensor imaging reveals perforant path degradation in aged humans in vivo. Proc Natl Acad Sci U S A. 2010; 107(28):12687-91. PMC: 2906542. DOI: 10.1073/pnas.1002113107. View

15.

Agis-Balboa R, Guidotti A, Pinna G . 5α-reductase type I expression is downregulated in the prefrontal cortex/Brodmann's area 9 (BA9) of depressed patients. Psychopharmacology (Berl). 2014; 231(17):3569-80. PMC: 6223254. DOI: 10.1007/s00213-014-3567-5. View

16.

Taylor A, Fishman L . Corticotropin-releasing hormone. N Engl J Med. 1988; 319(4):213-22. DOI: 10.1056/NEJM198807283190405. View

17.

Pinna G, Costa E, Guidotti A . Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmacology (Berl). 2006; 186(3):362-72. DOI: 10.1007/s00213-005-0213-2. View

18.

Uzunova V, Sheline Y, Davis J, Rasmusson A, Uzunov D, Costa E . Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci U S A. 1998; 95(6):3239-44. PMC: 19726. DOI: 10.1073/pnas.95.6.3239. View

19.

Singh C, Liu L, Wang J, Irwin R, Yao J, Chen S . Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice. Neurobiol Aging. 2011; 33(8):1493-506. PMC: 3232295. DOI: 10.1016/j.neurobiolaging.2011.06.008. View

20.

Guo A, Petraglia F, Criscuolo M, Ficarra G, Nappi R, Palumbo M . Evidence for a role of neurosteroids in modulation of diurnal changes and acute stress-induced corticosterone secretion in rats. Gynecol Endocrinol. 1995; 9(1):1-7. DOI: 10.3109/09513599509160184. View