@article{9ac1e259fa874c7ea82ff0433eb371b2,
title = "Allopregnanolone: Regenerative therapeutic to restore neurological health",
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.",
keywords = "Allopregnanolone, Neurogenesis, Neurosteroids, Regenerative therapeutic",
author = "Hernandez, {Gerson D.} and Brinton, {Roberta D.}",
note = "Funding Information: This research has been suppported by the National Institute on Aging , grant/award numbers: UF1AG046148 , U01AG031115 , U01AG047222 , P50AG05142 , R01AG063826 ; and, Alzheimer Drug Discovery Foundation grant 20150701.01 . Funding Information: Neuroendocrine homeostasis and stress response are mainly dependent upon the functioning of the hypothalamic–pituitary–adrenal (HPA) axis. An essential regulator of the HPA axis is the corticotropin-releasing hormone (CRH) secreted by the hypothalamus, which promotes the secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary gland, which in turn promotes the secretion of corticosteroids by the adrenal glands (Taylor and Fishman, 1988). The main glucocorticoid, cortisol, acts on many organs and brain regions, mainly exerting negative feedback on the hypothalamus, pituitary, and hippocampus. The dysregulation of the HPA axis as a result of chronic stress has been implicated in the etiology of affective disorders such as anxiety and depression (De Kloet, Vreugdenhil, Oitzl and Jo{\"e}ls, 1997; Holsboer and Barden, 1996; Swaab et al., 2005), and various neuropsychiatric disorders have been characterized by fluctuations in the levels of neurosteroids (Engel and Grant, 2001; Miczek, Fish and De Bold, 2003; Paul and Purdy, 1992; Zorumski, Paul, Izumi, Covey and Mennerick, 2013).Collectively, the work cited above laid the foundation and prompted further research to develop neurosteroids as therapeutic agents. Consequently, a therapeutic development program recently yielded an exogenous formulation of allopregnanolone (Brexanolone) for affective disorders. Brexanolone has been granted a “breakthrough therapy designation” by the FDA for the treatment of post-partum depression (Azhar Y, 2020; Meltzer-Brody et al., 2018). Two separate clinical trials testing brexanolone in women with postpartum depression used a continuous intravenous (IV) titration infusion regimen for up to 60 hours, which resulted in significant and clinically meaningful reductions in Hamilton Rating Scale (HAM-D) for Depression scores compared to placebo (Meltzer-Brody et al., 2018). However, the pattern of adverse events leading to dose reductions or interruptions in the trials show that most were related to excessive sedation or loss of consciousness, which is expected with such a dosing regimen. Brexanolone has since been further developed as an oral formulation with early evidence for improving symptoms of depression, as measured by HAM-D scores, in a phase 3 clinical trial in women with postpartum depression (Kristina M. Deligiannidis et al., 2021).This research has been suppported by the National Institute on Aging, grant/award numbers: UF1AG046148, U01AG031115, U01AG047222, P50AG05142, R01AG063826; and, Alzheimer Drug Discovery Foundation grant 20150701.01. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = nov,
doi = "https://doi.org/10.1016/j.ynstr.2022.100502",
language = "English (US)",
volume = "21",
journal = "Neurobiology of Stress",
issn = "2352-2895",
publisher = "Elsevier BV",
}