Neurosteroids or neuroactive steroids are steroids synthesized within the brain and modulate neuronal excitability.
The term was coined by the French physiologist Etienne Baulieu.
Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury.
What are the Different Types of Neurosteroids?
- Inhibitory
- Cause inhibitory actions on neurotransmission.
- Act as positive allosteric [binding at different site than meant for actual receptor] modulators of the GABA-A receptor
- Cause following effects
- Antidepressant
- Relieve anxiety
- Reduce stress
- Help in sleep
- Anticonvulsant
- Neuroprotective and neurogenic effects.
- Examples
- Tetrahydrodeoxycorticosterone (THDOC)
- Androstane 3α-androstanediol
- Cholestane
- Cholesterol
- Pregnanes – pregnanolone, allopregnanolone
- Excitatory
- Excitatory effects on neurotransmission.
- Act by following mechnisms
- Potent negative allosteric modulators of the GABAA receptor
- Weak positive allosteric modulators of the NMDA receptor
- Agonist of the σ1 receptor
- Effects
- Antidepressant
- Cause anxiety
- Enhance memory and cognition
- Act as convulsant
- Neuroprotective, and neurogenic effects
- Examples
- Sulfated pregnanes- Pegnenolone sulfate (PS), Epipregnanolone, Isopregnanolone (sepranolone)
- Adrostanes- dehydroepiandrosterone (DHEA) or prasterone), and dehydroepiandrosterone sulfate (DHEAS) or prasterone sulfate
- Cholestane
- Pheromones
- Influence hypothalamic function via activation of vomeronasal receptor cells.
- Include – Androstanes androstadienol, androstadienone, androstenol, and androstenon
- Other
- Pregnenolone, progesterone, estradiol and corticosterone
- These do not modulate the GABA-A or NMDA receptors
- Affect various other cell surface receptors and non-genomic targets
Many of these agents like pregnenolone, progesterone, corticosterone, deoxycorticosterone, DHEA, and testosterone, are metabolized into other neurosteroids and thus function as proneurosteroids.
Biosynthesis
Neurosteroids are A-ring reduced metabolites of the steroid hormones progesterone, deoxycorticosterone and testosterone.
The reduction of the parent steroid by is by enzyme 5α-reductase and 3α-hydroxysteroid oxidoreductase. The latter enzyme has more activity and the former one becomes the rate-limiting.
These conversion steps occur in peripheral tissues such as reproductive endocrine tissues, liver, and skin that are rich in the two reducing activities.
These can readily cross the blood-brain barrier, those synthesized in peripheral tissues accumulate in the brain.
Studies have also reported biosynthetic enzymes to be present in the human brain.
The biosynthesis of neurosteroids is controlled by the translocator protein formerly called peripheral or mitochondrial benzodiazepine.
How Neurosteroids Carry Their Effects?
Neurosteroids carry their effects mainly through non-genomic rapid action [ion channels and membrane receptors] in the brain. This is especially true for acute effects.
Chronic effects are due to both genomic (classical intracellular steroid receptors) and non-genomic rapid actions.
The genomic effects of neurosteroids are due to their metabolic interconversion to traditional hormones.
Most of the effects are though ligand-gated ion channels, especially GABA-A receptors.
The GABA-A receptor is a major target of neurosteroids.
The neurosteroids can be positive or negative regulators of GABA-A receptor function, depending on the chemical structure of the steroid molecule
The GABA-A receptor is a subtype of the receptor for the neurotransmitter GABA and mediates the bulk of synaptic inhibition in the central nervous system.
Examples of neurosteroid with positive modulation of GABA-A receptors are allopregnanolone, THDOC, and androstanediol.
In contrast, compounds such as progenolone sulphate which are sulfated at C3 have an inhibitory effect on GABA-A receptors. For example, pregnenolone sulfate and dehydroepiandrosterone
While neurosteroids modulate most GABA-A receptor isoforms, benzodiazepines act only on selected GABAA receptors.
At high concentrations, neurosteroids can directly activate GABA-A receptor channels even in the absence of GABA, an action similar to barbiturates.
Other receptors where neurosteroids can act on are the N-methyl-D-aspartate (NMDA) type glutamate receptors and sigma receptors.
Sulfated neurosteroids pregnenolone sulfate [PS] and dehydroepiandrosterone [DHEAS] have been shown to be potent agonists at NMDA receptor complex.
Physiological Functions and Potential Uses
Neurosteroids are involved in a number of physiological processes. These physiological effects form the basis of the potential for their therapeutic use.
Though the possibilities are numerous, the full potential is yet to be tapped, if possible, as most of the studies are still in the experimental phase.
In the following text, we discuss the physiological effects and the therapeutic interventions which may be possible for these functions.
Epilepsy
Non-sulfated compounds are protective against following seizures in experimental animal studies
- Induced GABA-A receptor antagonists
- Pilocarpine-induced limbic seizures
- Kindled seizures
In contrast, the sulfated neurosteroids PS and DHEAS have proconvulsant properties.
Ganaxolone is a synthetic analog of allopregnanolone that has been proved to be an effective anticonvulsant in human clinical trials for the treatment of epilepsy
Catamenial epilepsy
Catamenial epilepsy is the exacerbations of seizures at the time of menstruation or at other phases of the menstrual cycle.
Currently, there is no specific drug therapy for catamenial epilepsy but there is evidence that endogenous neurosteroids substantially influence seizure susceptibility.
Thus progesterone and neurosteroids, may provide rational therapy for catamenial epilepsy.
Anxiety
Neurosteroids such as allopregnanolone and Tetrahydrodeoxycorticosterone are potent anxiolytic agents. Progesterone too has shown anxiolytic activity in animal models.
Synthetic analogs of allopregnanolone have also shown to be anxiolytic.
It has been found that treatment with fluoxetine increases brain allopregnanolone levels.
In patients of panic attacks, there is a decrease in allopregnanolone levels. Increased levels of neurosteroids may counteract the occurrence of spontaneous panic attacks.
The sulphated neurosteroids PS and DHEAS have been shown to be anxiogenic effects
Therefore, the replacement of neurosteroids by synthetic analogs or a substance that stimulates stimulation of endogenous ones could be a promising strategy.
Premenstrual syndrome
The premenstrual syndrome consists of emotional and physical symptoms in the second half of the menstrual cycle.
It is thought that allopregnanolone could play an important role in the pathophysiology of premenstrual syndrome.
Though natural progesterone supplements have not been found to be beneficial, it is thought that neurosteroid could help.
Stress
Stress causes the release of corticotropin-releasing hormone from the hypothalamus which causes a release, which liberates ACTH from the anterior pituitary.
This enhances the synthesis of adrenal deoxycorticosterone which is a precursor of THDOC as well.
Plasma and brain levels of THDOC and allopregnanolone rise rapidly following acute stress.
Stress-induced neurosteroids affect seizure susceptibility.
Stress-induced seizures would thus occur when the balance of neurosteroids is shifted to favor proconvulsants rather than anticonvulsants.
Depression
Neurosteroids have a crucial role in depression.
Fluoxetine is a selective serotonin reuptake inhibitor and widely used antidepressant. It increases brain levels of allopregnanolone.
Direct administration of allopregnanolone has been found to alleviate depressive behavior in animals.
In patients of depression, plasma and cerebrospinal fluid allopregnanolone levels are decreased but while plasma concentrations of tetrahydrodeoxycorticosterone are higher.
These levels get corrected with effective treatment with fluoxetine.
Sulfated neurosteroids like PS and DHEAS as well as DHEA have clear antidepressant effects in animals and humans. These two also enhance cognition in animals.
DHEA is a precursor of DHEAS and has been widely investigated as a novel antidepressant. Interestingly, it is a popular food supplement.
Postpartum depression is a type of depression that occurs after the delivery of the child.
Pregnancy is associated with a marked rise in progesterone-derived neurosteroid levels, which decline rapidly after delivery and this withdrawal is thought to play a key role.
Learning and Memory
Neurosteroids also modulate learning and memory processes.
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.
In preclinical studies, administration of DHEA and DHEAS improved retention performance in aged animals
Inhibitors of steroid sulfatase, an enzyme that converts sulphated steroids into free steroids. Increasing the levels of endogenous sulfated neurosteroids via the inhibition of steroid sulfatase activity may enhance learning and memory function.
Alcohol Tolerance and Withdrawal
There is a correlation between the alcohol-induced allopregnanolone production in the brain and behavioral and neural effects of alcohol.
It is suggested that neurosteroids contribute to alcohol action. The identification of the right signal may lead to further development in this field.
Gender Difference in Brain Disorders
Anxiety and depression affect more women than men.
The incidence of epilepsy is generally higher in males than in females.
There are other conditions where there is a gender difference between brain disorders and neurosteroids are thought to be responsible.
But this issue requires further research.
References
- Do Rego JL, Seong JY, Burel D, Leprince J, Luu-The V, Tsutsui K, Tonon MC, Pelletier G, Vaudry H. Neurosteroid biosynthesis, enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Frontiers in Neuroendocrinology. 2009;30:259–301.
- Hosie AM, Clarke L, da Silva H, Smart TG. Conserved site for neurosteroid modulation of GABA-A receptors. Neuropharmacology. 2009;56:149–154.
- Joels M. Steroid hormones and excitability in the mammalian brain. Frontiers in Neuroendocrinology. 1997;18:2–48.
- Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA. Neurosteroid modulation of GABAA receptors. Progress in Neurobiology. 2003;71:67–80.
- Reddy DS. Pharmacology of endogenous neuroactive steroids. Critical Reviews in Neurobiology. 2003;15:197–234.
2