Neurosteroids: Endogenous Role in the Human Brian and Therapeutic Potentials – free full-text /PMC3139029/ – July 2011
This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and therapeutic potentials.
Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful antiseizure activity in diverse animal models.
Neurosteroids increase both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety and stress.
This is exactly the kind of information I was looking for: a potential new treatment for the anxiety that has tormented me for decades.
Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy and other brain disorders.
Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.
Based on structural features, neurosteroids can be classified as
- pregnane neurosteroids, such as allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC),
- androstane neurosteroids, such as androstanediol and etiocholanone, and
- sulfated neurosteroids, such as pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS).
Steroid hormones have long been recognized to have sedative, anesthetic and antiseizure properties in animals and humans
Studies during the past two decades have uncovered that progesterone and deoxycorticosterone serve as precursors for the endogenous neurosteroids
- allopregnanolone (5α-pregnane-3α-ol-20-one) and
- THDOC (5α-pregnane-3α,21-diol-20-one), respectively
Testosterone-derived androgens such as androstanediol (5α-androstane-3α,17β-diol) and estradiol can be considered as neurosteroids
Moreover, neurosteroids are not themselves active at intracellular steroid receptors. They modulate brain excitability primarily by interaction with neuronal membrane receptors and ion channels, principally GABA-A receptors
Neurosteroids are endogenous regulators of neuronal excitability, and therefore provide tremendous opportunities for developing therapeutic approaches
Physiological and pharmacological effects and therapeutic potentials
The physiological and pharmacological profile of major neurosteroids is listed in Table 1.
In general, neurosteroids that are 3α-hydroxy-pregnane derivatives such as allopregnanolone, pregnanolone, and THDOC (allotetrahydrodeoxycorticosterone) elicit sedative, anxiolytic, and anticonvulsant actions.
PS (pregnenolone sulfate) and DHEAS (dehydroepiandrosterone sulfate) are excitatory and produce memory enhancing and anxiogenic effects.
Pharmacological profile of major neurosteroids.
Neurosteroid Pharmacological Actions Mechanism of Action Allopregnanolone Sedative-hypnotic
Potentiation of GABA-A receptor function THDOC Sedative-hypnotic
Potentiation of GABA-A receptor function Androstanediol Anxiolytic, anticonvulsant Potentiation of GABA-A receptor function Pregnenolone sulfate Anxiogenic, proconvulsant
Memory enhancing, neuroprotection
Inhibition of GABA-A receptor function
Enhanced NMDA receptor function
Dehydroepiandrosterone sulfate Anxiogenic, proconvulsant
Inhibition of GABA-A receptor function
Enhanced NMDA receptor function
Synthetic neurosteroids that show better pharmacokinetics and efficacy are evaluated for sedative and anxiolytic (minaxolone), anesthetic (alphaxolone) and antiepileptic (ganaxolone) effects (Table 2).
Therapeutic potentials of synthetic neurosteroids.
Agent Chemical Structure Major Indication Status Alphaxolone Anesthetic Used in veterinary anesthesia Minaxolone Sedative Anxiety Phase I/II Ganaxolone Epilepsy Phase IIB trials
There is considerable evidence for an involvement of neurosteroids in the etiology of anxiety disorders.
Neurosteroids such as allopregnanolone and THDOC are potent anxiolytic agents
Progesterone also has anxiolytic activity in animal models. Administration of progesterone produces similar sedative-anxiolytic effects in men and women
Anxiolytic properties have also been demonstrated with the use of synthetic analogs of allopregnanolone
Treatment with fluoxetine, a specific serotonin uptake inhibitor, dose-dependently increases brain allopregnanolone levels.
They only talk about this oldest version of the SSRI antidepressants that are used these days. I wonder if it’s because it’s the only one they studied or because it has a specific effect that’s lacking in all the others.
Neurosteroidogenic compounds might represent novel drugs for anxiety. The sulphated neurosteroids PS (pregnenolone sulfate) and DHEAS have been shown to be anxiogenic effects
DHEAS is synthesized in the brain from DHEA, an adrenal steroid that decreases with aging.
PS (pregnenolone sulfate) had a biphasic response on the plus-maze;
- at higher doses it caused an anxiogenic response while
- at lower doses it produced an anxiolytic response
PS is present in brain at a relatively high concentration compared with many other neurosteroids and is presumably generated by local steroid sulfotransferases since charged steroid sulfates are unlikely to cross the blood–brain barrier.
Progesterone-derived neurosteroids may be important for the clinical manifestations of PMS.
In normal women, allopregnanolone varies very similarly to progesterone throughout the menstrual cycle with greater levels in the luteal phase than in the follicular phase
Thus, allopregnanolone could play an important role in the pathophysiology of PMS.
Neurosteroids are released during physiological stress. Plasma and brain levels of THDOC and allopregnanolone rise rapidly following acute stress.
Both circulating and brain levels of allopregnanolone and THDOC reach their peak during stress. Acute stressors such as swimming, foot shock or carbon dioxide exposure elicit an increase in allopregnanolone and THDOC concentrations in plasma and in brain.
Stress-induced increases in THDOC peak between 10 and 30 min after stressor in normal animals. Thus, THDOC can be considered a component of the “hypothalamic-pituitary-adrenal (HPA) axis” stress response system.
Neurosteroids have a crucial role in depression. Animal studies showed that fluoxetine, a selective serotonin reuptake inhibitor and widely used antidepressant, increases brain levels of allopregnanolone.
while direct administration of allopregnanolone alleviates depressive behavior in animal models of depression. Consequently, there is emerging interest on the role of allopregnanolone in mediating antidepressant actions of fluoxetine and in the pathophysiology of depression.
major depression in humans is associated with a dysequilibrium of endogenous neurosteroids.
- In depressed patients, plasma and cerebrospinal fluid allopregnanolone levels are reduced, while plasma concentrations of THDOC are higher.
- fluoxetine-like antidepressants markedly elevate levels of allopregnanolone
- Sulfated neurosteroids PS and DHEAS as well as DHEA have clear antidepressant effects in animals and humans
- PS and DHEAS also enhance cognition in animals
- DHEA, a precursor of DHEAS and a dietary supplement, has been widely investigated as a novel antidepressant
However, studies investigating DHEA and DHEAS concentrations in depression have yielded inconsistent results with both increase and decrease during major depression. Overall, there are indications that adjunct DHEA could produce beneficial effects in patients with depression.
Learning and memory
Neurosteroids have been widely recognized to modulate learning and memory processes in young, aged and in pharmacological models of amnesia.
Pregnenolone, PS, DHEA, and DHEAS increased memory when injected systemically, centrally or into amygdala. Normal aging and cognitive dysfunction is associated with decreased levels of DHEA and DHEAS.
Consequently, neurosteroids such as DHEA and DHEAS are implicated to play a role in the manifestations of Alzheimer’s disease. There is evidence that the concentrations of DHEA and DHEAS are decreased in patients suffering from Alzheimer’s disease.
Interestingly, DHEA is available in the market as an antiaging drug. In preclinical studies, administration of DHEA and DHEAS improved retention performance in aged animals.
Pregnenolone treatment as adjunctive for cognitive and negative symptoms in patients with schizophrenia has been investigated (Marx et al., 2009). Patients receiving pregnenolone demonstrated significantly greater improvements in cognitive scores, indicating the promising therapeutic potential of neurosteroids for these conditions.
Conclusions and future perspectives
Neurosteroids are endogenous modulators of neural excitability.
The major pharmacological effects of neurosteroids occur largely as a result of their allosteric potentiation of GABA-A receptors.
Experimental and clinical evidence suggest an endogenous role for neurosteroids in various neurological and psychiatric conditions such as epilepsy, anxiety and depression.