Allopregnanolone: Regenerative therapeutic to restore neurological health

[madman]

Allopregnanolone: Regenerative therapeutic to restore neurological health (2023)
Gerson D. Hernandez, Roberta D. Brinton


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 the stress ends indicates 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 on 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.




1. Introduction

The central role of the brain in the neurobiology of stress and adaptation has been well documented by Bruce McEwen over many years (B. S. McEwen, 2006, 2007, 2016; Bruce S. McEwen et al., 2015; B. S. McEwen and Gianaros, 2010, 2011). Moreover, the relationship between stress, chronic inflammation, and neurodegenerative disease is well established. 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 (Heneka et al., 2015; Herrera et al., 2015; Hiller, Quinn and Schmidt, 2017; Holmes, 2013; Justice, 2018; Madore, Yin, Leibowitz and Butovsky, 2020; Mishra and Brinton, 2018; Swaab, Bao and Lucassen, 2005; Vyas et al., 2016). According to McEwen and colleagues, 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 the stress ends indicates failed resilience. The underlying mechanisms of plasticity and vulnerability of the brain provide the basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline. (Bruce S. McEwen et al., 2015).




2. Neurosteroids and stress


3. Allopregnanolone and stress


4. Neurogenesis and allopregnanolone




5. Conclusions

The neurobiology of stress plays an important role in chronic inflammation and the development of neurodegenerative diseases. 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 on neurodegenerative disorders like Alzheimer’s disease. This target has enabled the development of allopregnanolone as a regenerative therapeutic to restore neurological health.

 

[madman]

Fig. 1. Allopregnanolone biosynthetic pathway. Steroidogenesis of allopregnanolone starting from cholesterol metabolism. The brain must synthesize its own cholesterol from acetyl-CoA of peripherally circulating cholesterol. In the mitochondria, it is converted into pregnenolone by the cytochrome P450 side-chain cleavage enzyme. It is then converted in the cytosol to progesterone. Allo is a reduced metabolite of progesterone synthesized in the adrenal cortex, gonads, and central nervous system.

 

[madman]

Fig. 2. Allopregnanolone regenerative mechanism of action. Allo activates the GABAA receptor complex promoting the efflux of chloride (CI− ) ions from neural progenitor and neural stem cells. Extrusion of Cl− from the intracellular compartment causes membrane depolarization and activation of voltage-dependent L-type calcium (Ca2+) channels. The resulting rise in intracellular Ca2+ activates calcium-dependent kinases that will ultimately lead to the regulation of gene expression and protein synthesis of cell cycle proteins.

 

[madman]

Fig. 3. Reversing altered brain structure and function. Chronic stress results in decreased levels of allopregnanolone which affects brain structure (i.e., brain atrophy) and function. Increased levels of allopregnanolone result in neural proliferation and improved brain structure and function.

 

[madman]

Fig. 4. Allopregnanolone’s translational development progress: From early discovery to current clinical testing.

 

[Nelson Vergel]

From Chatgpt

Allopregnanolone is a neurosteroid that acts as a positive allosteric modulator of gamma-aminobutyric acid (GABA) receptors in the brain. It has been linked to various effects, including anxiolytic (anti-anxiety), sedative, and neuroprotective properties. While there are no guaranteed methods to increase allopregnanolone levels, here are some factors that may potentially influence its production:

1. Pharmacological Intervention: Certain medications, such as selective serotonin reuptake inhibitors (SSRIs) and certain anxiolytic drugs, have been found to increase allopregnanolone levels in some individuals. However, these medications should only be used under the guidance of a healthcare professional.

2. Exercise: Regular physical exercise has been associated with increased levels of allopregnanolone in some studies. Engaging in aerobic exercises and maintaining an active lifestyle may potentially have positive effects on allopregnanolone production.

3. Stress Reduction: Chronic stress can negatively impact allopregnanolone levels. Engaging in stress-reducing activities, such as mindfulness meditation, deep breathing exercises, and getting adequate sleep, may potentially help support healthy allopregnanolone levels.

4. Diet and Nutrition: Certain dietary factors, such as consuming foods rich in omega-3 fatty acids (e.g., fatty fish, flaxseed) and maintaining a balanced diet with adequate intake of vitamins and minerals, may support healthy brain function and potentially influence allopregnanolone levels indirectly.

It's important to note that the specific effects and interactions of allopregnanolone are complex and can vary among individuals. Additionally, altering allopregnanolone levels should be approached with caution and under the guidance of healthcare professionals, as it may have significant effects on the body and brain function. If you are seeking to address specific health concerns, it's advisable to consult a healthcare provider who can provide personalized guidance based on your individual circumstances.

 

[Nelson Vergel]

Allopregnanolone: An overview on its synthesis and effects

Abstract Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and...

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[Nelson Vergel]

How Can I Increase My Allopregnanolone ?

We know that pregnenolone and progesterone increase allopregnanolone. Do you know any other hormones that increase allopregnanolone?

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