Neurosteroid
Neurosteroids, also known as neuroactive steroids, are
Classification
Based on differences in activity and structure, neurosteroids can be broadly categorized into several different major groupings.[3]
Inhibitory neurosteroids
These neurosteroids exert
Major examples include
Excitatory neurosteroids
These neurosteroids have
Major examples include the pregnanes
Pheromones
Pheromones are neurosteroids that influence brain activity, notably hypothalamic function, via activation of vomeronasal receptor cells.[18][19][20]
Possible human pheromones include the androstanes androstadienol, androstadienone, androstenol, and androstenone and the estrane estratetraenol.
Other neurosteroids
Certain other endogenous steroids, such as pregnenolone,[21] progesterone,[22][23] estradiol,[5] and corticosterone are also neurosteroids. However, unlike those listed above, these neurosteroids do not modulate the GABAA or NMDA receptors, and instead affect various other cell surface receptors and non-genomic targets. Also, many endogenous steroids, including pregnenolone, progesterone, corticosterone, deoxycorticosterone, DHEA, and testosterone, are metabolized into (other) neurosteroids, effectively functioning as so-called proneurosteroids.
Biosynthesis
Neurosteroids are synthesized from
Function
Some major known
Acute stress elevates the levels of inhibitory neurosteroids like allopregnanolone, and these neurosteroids are known to counteract many of the effects of stress.
It is thought that fluctuations in the levels of inhibitory neurosteroids during the
Elevated levels of inhibitory neurosteroids, namely allopregnanolone, can produce paradoxical effects, such as negative mood, anxiety, irritability, and aggression.[39][40][41][42] This appears to be because these neurosteroids, like other positive allosteric modulators of the GABAA receptor such as the benzodiazepines, barbiturates, and ethanol,[34][42] possess biphasic, U-shaped actions – moderate levels (in the range of 1.5–2 nM/L total alloprogesterone, which are approximately equivalent to luteal phase levels) inhibit the activity of the GABAA receptor, while lower and higher concentrations facilitate the activity of the receptor.[40][41]
Biological activity
Sigma-1 receptor
| Compound | Ki (nM) | Action | Species | Ref |
|---|---|---|---|---|
| Progesterone | 268 | Antagonist | Guinea pig | [44][45] |
| Deoxycorticosterone | 938 | Unknown | Guinea pig | [44][45] |
| Testosterone | 1,014 | Unknown | Guinea pig | [44][45] |
| Pregnenolone | ND | Agonist | ND | ND |
| Pregnenolone sulfate | 3,198 | Agonist | Guinea pig | [44][45] |
| DHEA | 3,700 | Agonist | ? | [45] |
| DHEA-S | ND | Agonist | ND | ND |
| Corticosterone | 4,074 | Unknown | Guinea pig | [44] |
Therapeutic applications
Anesthesia
Several synthetic neurosteroids have been used as
Ganaxolone
The neurosteroid ganaxolone, an analog of the progesterone metabolite allopregnanolone, has been extensively investigated in animal models and is currently in clinical trials for the treatment of epilepsy. Neurosteroids, including ganaxolone have a broad spectrum of activity in animal models.[46] They may have advantages over other GABAA receptor modulators, notably benzodiazepines, in that tolerance does not appear to occur with extended use.[47][48]
A randomized, placebo controlled, 10-week phase 2 clinical trial of orally administered ganaxolone in adults with partial onset seizure demonstrated that the treatment is safe, well tolerated and efficacious.[9] The drug continued to demonstrate efficacy in a 104-week open label extension. Data from non-clinical studies suggest that ganaxolone may have low risk for use in pregnancy. In addition to use in the treatment of epilepsy, the drug has potential in the treatment of a broad range of neurological and psychiatric conditions. Proof-of-concept studies are currently underway in posttraumatic stress disorder and fragile X syndrome. Ganaxolone was approved for medical use in the United States in March 2022.
Catamenial epilepsy
Researchers have suggested the use of so-called "neurosteroid replacement therapy" as a way of treating
Allopregnanolone
Allopregnanolone (SAGE-547) is under development as an
Other applications
Role in antidepressant action
Certain antidepressant drugs such as fluoxetine and fluvoxamine, which are generally thought to affect depression by acting as selective serotonin reuptake inhibitors (SSRIs), have also been found to normalize the levels of certain neurosteroids (which are frequently deficient in depressed patients) at doses that are inactive in affecting the reuptake of serotonin. This suggests that other actions involving neurosteroids may also be at play in the effectiveness of these drugs against depression.[56][57]
The
Benzodiazepine effects on neurosteroids
See also
References
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Further reading
- Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S (December 2005). "Neurosteroid access to the GABAA receptor". The Journal of Neuroscience. 25 (50): 11605–13. PMID 16354918.
- Wang JM, Johnston PB, Ball BG, Brinton RD (May 2005). "The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression". The Journal of Neuroscience. 25 (19): 4706–18. PMID 15888646.
- Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, Watanabe H, Costa E, Guidotti A (February 2001). "Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation". Proceedings of the National Academy of Sciences of the United States of America. 98 (5): 2849–54. PMID 11226329.
- Melcangi RC, Celotti F, Martini L (March 1994). "Progesterone 5-alpha-reduction in neuronal and in different types of glial cell cultures: type 1 and 2 astrocytes and oligodendrocytes". Brain Research. 639 (2): 202–6. S2CID 37105244.
- Corpéchot C, Robel P, Axelson M, Sjövall J, Baulieu EE (August 1981). "Characterization and measurement of dehydroepiandrosterone sulfate in rat brain". Proceedings of the National Academy of Sciences of the United States of America. 78 (8): 4704–7. PMID 6458035.
- Reddy D, Rogawski MA (2012). "Neurosteroids — Endogenous regulators of seizure susceptibility and role in the treatment of epilepsy". In Noebels JL, Avoli M, Rogawski MA, et al. (eds.). Jasper's Basic Mechanisms of the Epilepsies (4th ed.). Bethesda (MD): National Center for Biotechnology Information. PMID 22787590.