4.4 Article

Allopregnanolone: Regenerative therapeutic to restore neurological health

Journal

NEUROBIOLOGY OF STRESS
Volume 21, Issue -, Pages -

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.ynstr.2022.100502

Keywords

Neurosteroids; Allopregnanolone; Regenerative therapeutic; Neurogenesis

Categories

Funding

  1. National Institute on Aging
  2. Alzheimer Drug Discovery Foundation
  3. [UF1AG046148]
  4. [U01AG031115]
  5. [U01AG047222]
  6. [P50AG05142]
  7. [R01AG063826]
  8. [20150701.01]

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Chronic stress can alter brain structure and function, potentially contributing to the development and progression of neurodegenerative diseases. The remodeling of neural architecture in response to stress can indicate successful adaptation, but persistent changes after stress ends suggest failed resilience. The hypothalamic-pituitary-adrenal axis plays a crucial role in neuroendocrine homeostasis and stress response. Neurosteroids, such as allopregnanolone, fluctuate depending on the duration of stress and may have therapeutic potential for neurodegenerative disorders like Alzheimer's disease, particularly in promoting neuroregeneration.
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 neu-rogenesis, 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.

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