Allopregnanolone

Allopregnanolone (also known as tetrahydroprogesterone) is a neuroactive neurosteroid, i.e. a steroid produced naturally in the body. These modulate neuronal activity in a subtle way.

A review explains the neuromodulatory effects of neurosteroids such as pregnenolone, progesterone and allopregnanolone on the dopamine system and the associated deviant behavioral phenotypes.¹

Acute stress increases and chronic stress reduces neurosteroid synthesis.¹

The levels and effects of allopregnanolone are gender-specific²
Allopregnanolone has low bioavailability and extensive hepatic metabolism, which limits its usefulness as a drug.²

Antagonist: Isoallopregnanolone
Similar substances: brexanolone, ganaxolone, zuranolone

• 1. Allopregnanolone synthesis
• 2. 5α-Reductase a starting point for influencing the dopamine system?
• 3. Allopregnanolone and stress
• 4. What influences allopregnanolone
• 5. How allopregnanolone works
• 6.Allopregnanolone and ADHD

1. Allopregnanolone synthesis¶

The following presentation is primarily based on the explanation by Scheggi et al.¹

AIlopregnanolone is a potent positive allosteric modulator of the GABAA receptor, through which it rapidly and relevantly regulates brain excitability.³

Allopregnanolone synthesis:

• takes place in
  • Brain (mainly)
  • Ovaries
  • Placenta
  • Adrenal glands
• temporally in particular
  • during the entire menstrual cycle in the corpus luteum (maximum during the luteal phase under the influence of the luteinizing hormone)
  • in the placenta in the second half of pregnancy
    • on the neurological development processes of the fetus
    • to stabilize the mother’s mood
    • to regulate the mother’s stress response
• involved in psychological symptoms in
  - abrupt drop after birth; this can be triggered:⁴
  - postpartum depression in the mother
  - long-term negative effects on the neurobehavior of the offspring
  - prolonged stress can disrupt the responsiveness of the hypothalamic-pituitary-adrenal axis (HPA axis) in susceptible individuals⁵
  - causes reduced allopregnanolone synthesis in the adrenal glands
  - promotes risk of major depressive disorder (MDD) or post-traumatic stress disorder (PTSD)

Synthesis steps of allopregnanolone:

• /Step 1: Formation of cholesterol
  - is synthesized endogenously or arises from the degradation of lipoproteins.
  - is the rate-limiting step in the synthesis of all steroid classes
• /Step 2: Transfer of cholesterol through the mitochondrial membrane⁶
  • The transport from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM) is mediated by two important importer proteins:
    • the steroidogenic acute regulatory protein (StAR)
      • probably initiates the transfer of cholesterol into the mitochondria
    • the translocator protein (18 kDa, TSPO)
      • Binding point for StAR
      • supports the first steps of cholesterol transfer into the mitochondria
      • required to efficiently anchor cholesterol in the OMM and promote its shift to the IMM
• /Step 3: Cholesterol is catalyzed By CYP450scc and CYP11A1 to pregnenolone, the prodrug of all neurosteroids
• /Step 4: Pregnenolone is Converted to progesterone** in the cytosol by the enzyme 3β-hydroxysteroid dehydrogenase **.
• /Step 5: Progesterone is converted By the enzyme 5α-reductase (5αR) to 5α-dihydroprogesterone (5α-DHP)
  • 5aR is the rate-limiting step in the synthesis of 3α, 5α-steroid derivatives⁷
  • 5αR has 5 isoenzymes, of which only 5αR1 and 5αR2 are relevant in neurosteroid genesis
    • both isoenzymes are widely expressed in most key regions of the adult rat brain⁸⁹
    • Expression pattern and cellular localization differ in rodents
      • 5αR1 isoform in most regions of the forebrain in neurons, oligodendrocytes, microglia, type 1 astrocytes and Schwann cells
      • 5αR2 isoform widely distributed throughout the brain (forebrain to brainstem and cerebellum of the adult rat). in neurons, but not in glial cells
  • convert 5aR1 like 5aR2 (with different affinity)
    • Progesterone to 5α-dihydro derivative 5α-dihydroprogesterone (5α-DHP)
    • in addition, the dismantling of
      • Testosterone in 5-alpha-dihydrotestosterone (DHT, a potent androgen)
      • Aldosterone¹⁰
      • Dexamethasone¹⁰
      • Cortisol and corticosterone into less potent glucocorticoid receptor agonists¹⁰
  • 5aR inhibitors:
    • Inhibition has a very long-lasting effect (up to 10 years after discontinuation)¹¹
    • Finasteride
      • inhibits 5aR2 significantly more strongly than 5aR1
    • Dutasteride
      • inhibits 5aR1 and 5aR2 equally strongly
      • appears to have a better and more lasting effect on prostate hyperplasia than finasteride¹
• /Step 6: 5α-DHP is converted By the enzyme 3α-hydroxysteroid oxidoreductase (3α-HSOR) to allopregnanolone (3α, 5α-tetrahydroprogesterone, THP) and isoallopregnanolone (the 3β-isomer of allopregnanolone)

Allopregnanolone is therefore the end product of the 5α,3α metabolic pathway of pregnenolone via progesterone.

2. 5α-Reductase a starting point for influencing the dopamine system?¶

5α-reductase is therefore involved in allopregnanolone synthesis.
5αR-related neurosteroids improve behavioral abnormalities associated with hyperactivation of the mesostriatal dopamine system.¹

The 5α-reductase inhibitors (5α-RIs) finasteride (Propecia) and dutasteride are approved for the treatment of

• Symptoms of the lower urinary tract due to benign prostatic hyperplasia, with clear clinical efficacy

Finasteride is still approved for the treatment of

• Hair loss (androgenetic alopecia)

In principle, the undesirable side effects of these drugs are considered to be minimal. A subgroup of men report persistent adverse effects on sexual function to an extent that impairs quality of life, such as erectile dysfunction, numbness in the glans, reduced or absent libido, reduced or absent orgasmic sensation. Gynecomastia and depression have also been reported.¹² Anxiety reactions have also been noted as side effects.¹¹ Sleep problems and chronic pain can occur as withdrawal reactions.

The 5αR inhibitors influence some of the behavioral effects of D1 receptors in animal models.¹³

In several disorders associated with increased dopamine levels, a specific disorder of the 5αR enzyme pathway and a resulting imbalance of neuroactive steroids has been observed:

• Schizophrenia¹⁴¹⁵
• Tourette syndrome^1617181920
• post-traumatic stress disorder (PTSD)
• Cannabis addiction
• Fear²¹

Of note, these diseases are etiologically characterized by hyperdopaminergic states. In the next sections, we will present key preclinical and clinical findings that demonstrate how targeting neurosteroidogenesis within the 5α, 3α signaling pathway and/or exogenous administration of associated neuroactive steroids can significantly modulate dopamine transmission in brain regions and circuits closely associated with these psychiatric disorders.

5αR has been tested in tic disorder mouse models with high significance, construct validity and predictive power, such as the D1CT-7 mice.
In the D1CT-7 transgenic mice, the promoter region for the D1 receptor was fused to the enzymatic part of the cholera toxin subunit gene α1 (A1), resulting in sustained activation of Gs proteins. D1CT-7 mice show explosive, jerky movements of the head, trunk and limbs that strongly resemble tics. Consistent with sex differences in persons with ADHD, male D1CT-7 mice show more tic outbursts than females. In addition, twitching begins on postnatal day 16, when changes in the steroid profile begin that resemble adrenarche in primates.⁷

5αR inhibitors significantly reduce

• Dopamine
• Tic disorders

The authors suggest that increased 5αR activity early in development may lead to inappropriate activation of the “back door” for androgen synthesis from adrenarche to the end of puberty, and the resulting imbalances in steroid homeostasis may impair signaling of dopamine and other neurotransmitters, ultimately leading to the facilitation of tics and other behavioral abnormalities in tic disorders.⁷

3. Allopregnanolone and stress¶

Acute stress increases allopregnanolone, which in turn inhibits the HPA axis (as does cortisol). Allopregnanolone, like cortisol, is therefore a hormone that brings the HPA axis down again at the end of the stress reaction. Chronic stress, on the other hand, as it contributes to the development of neuropsychiatric disorders such as depression and anxiety, leads to a decrease in allopregnanolone levels, which impairs the ability to downregulate the HPA axis after its acute activation.²²

Acute stress (forced swimming, CO2 inhalation, foot shock, fixation, restraint stress) increases

• the allopregnanolone level in the plasma^{2223 24} and in the brain²³²⁴ of rodents
• pregnenolone levels in the brain, but not in plasma, in chronically stressed animals²³

Chronic (mild to severe) stress (forced swimming, social isolation, repeated restraint stress) reduced

• the allopregnanolone level²²²³
• pregnenolone levels in the brain, but not in plasma²³
  • An animal model of unpredictable chronic stress showed clear changes in the brain in relation to pregnenolone²³.

The ratio of brain level to plasma level of pregnenolone was significantly higher than that of allopregnanolone.²³²⁴
Pregnenolone brain levels were significantly higher in females than in males.²⁵

4. What influences allopregnanolone¶

• The competitive 3β-hydroxysteroid dehydrogenase (3β-HSD) inhibitor trilostane
  • increases pregnenolone in the hippocampus and PFC, which correlates with its antidepressant effect³
• Antipsychotic neuroleptics (olanzapine, haloperidol, clozapine)
  • increase allopregnanolone in the hippocampus and cortex of rats²⁶²⁷³
  • increase pregnenolone in the hippocampus and cortex of rats²⁸
• acute administration of low doses of micronized progesterone reliably increases allopregnanolone levels

5. How allopregnanolone works¶

Allopregnanolone acts as

• highly effective positive allosteric modulator
  • of the GABAA receptor²⁹
    • Allopregnanolone shows an inverted-U effect profile on GABAA³⁰³¹
      • Moderate increases (1.5-2 nmol/L total allopregnanolone, typical for luteal phase) inhibit GABAA
      • lower and higher concentration increases stimulate GABAA
  • of the GABAA-ρ receptor³²³³
• negative allosteric modulator of
  • nACh receptors³⁴ (like progesterone)
  • 5-HT3 receptor³⁵
• Agonist of the membrane-bound progesterone receptors mPRδ, mPRα and mPRβ³⁶³⁷
  • Activity at these receptors is an order of magnitude stronger than at the GABAA receptor
• Activator of the pregnane X receptor³⁸ (like progesterone)

Allopregnanolone does not or barely binds to

• NMDA receptor³⁸
• AMPA receptor³⁸
• Kainate receptor³⁸
• Glycine receptors³⁸
• nuclear progesterone receptor³⁸
  • indirect effect on the progesterone receptor after intracellular oxidation of allopregnanolone to the PR agonist 5α-dihydroprogesterone³⁹⁴⁰

Allopregnanolone

• reduces the evoked dopamine release depending on sex and estrus phase⁴¹
• inhibits basal and stress-induced dopamine release in the PFC and nucleus accumbens.⁴²
• increases dopamine release and the dopaminergic response to morphine in the nucleus accumbens⁴³

Allopregnanolone works

• antipsychotic¹⁴
• antidepressant⁴⁴⁴⁵⁴⁶
• stress-relieving
• anxiolytic⁴⁷
  at the GABAA receptors⁴⁷²
  • increases the GABAergic tone
  • resulting in a behavioral profile similar to that of dopamine receptor antagonists, e.g. the neuroleptic haloperidol⁴⁸

The 3β-methylated analog of allopregnanolone

• reduces PTSD-like behavior in mice triggered by social isolation⁴⁹

Pregnenolone works

• anxiolytic
• antidepressant²³
• reduces schizophrenia-like cognitive impairment in dopamine transporter knockout mice⁵⁰

6.Allopregnanolone and ADHD¶

Reduced serum levels of allopregnanolone were found in children with ADHD⁵¹

Methylphenidate caused⁵²

• a doubling of the allopregnanolone level in ADHD-I without depressive symptoms (27.26 ± 12.90 vs. 12.67 ± 6.22 ng/ml, morning values)
• mPH lowered the allopregnanolone level in the presence of additional depressive symptoms

Administration of the neurosteroid ganaxolone to premature pigs prevented the development of ADHD symptoms.⁵³
Premature babies exhibit altered cerebral myelination. Allopregnanolone is an important building block for myelination. The administration of allopregnanolone to premature infants could help to prevent myelination damage⁵⁴

Prenatal stress in guinea pigs in late childhood caused hyperactivity in males and anxiety symptoms in females.
Postnatal administration of ganaxolone and emapunil after prenatal stress caused:⁵⁵

• (only) in females to avoid the symptoms associated with stress (in this case anxiety symptoms)
• Emapunil restored the mature myelin content in both sexes
• Emapunil reversed the disorders of the oligodendrocyte sequence in the female offspring