This document discusses neuroactive steroids, which are steroids synthesized in the brain or other endocrine glands that rapidly alter neuronal excitability through interaction with receptors. They can have inhibitory or excitatory effects and are involved in many neurological and psychiatric conditions. Neuroactive steroids are also implicated in sex differences in brain disorder susceptibility. While their roles are increasingly understood, key questions remain regarding their regulatory mechanisms and impact on specific brain conditions and gender differences. Further research is needed to clarify their molecular mechanisms of action and therapeutic potential.
2. ο Introduction
ο Definition
ο Classification
ο Biosynthesis
ο Mechanisms of action
ο Pharmacological actions
ο Therapeutic implications
ο Role in sex differences in susceptibility to brain
disorders
ο Conclusion & future perspectives
2
3. ο Neuroinflammation is a common feature of many CNS
pathologies - onset & progression
ο nerve dysfunction, degeneration & death.
3
Hormonal
Steroids
Peripheral glands
Neuroactive
steroids
4. ο aka Neuroactive steroids.
βSteroids synthesized from brain that act by rapidly
altering neuronal excitability through interaction
with ligand-gated ion channels and other cell surface
receptors.β
Neurosteroids = Brain
Neuroactive steroids = Brain + Endocrine glands
(adrenals, gonads)
4
5. ο βNeurosteroidsβ originally coined by the French
physiologist Etienne Baulieu.
ο βNeuroactive steroidsβ was first coined in 1992 by
Steven Paul and Robert Purdy.
ο Wide range of potential clinical applications
from sedation to treatment of epilepsy &
traumatic brain injury
5
11. ο NS synthesis is controlled by translocator protein:
18 kD
- found in peripheral tissues and brain.
- located in outer mitochondrial membrane
- favors transport of cholesterol to inner
mitochondrial membrane
ο promotes neurosteroid synthesis
11
12. ο Not active at intracellular steroid receptors.
ο Interact with neuronal membrane receptors and
ligand-gated ion channels - ππππ π receptors
ο Progesterone receptor (PR) knockout mice studies
demonstrate that β
Classical steroid receptor is not required for the
sedative, anxiolytic, & anticonvulsant activity of
progesterone & related NS
12
20. ο Broad-spectrum anticonvulsant agents.
ο Highly effective in the Pentylenetetrazol (PTZ) model
of epilepsy.
ο Sulfated NS (PS and DHEAS) are proconvulsants
- block GABAA receptors and facilitate NMDA
receptor functions.
ο Synthetic NS - rational alternative approach to
anti-convulsant therapy
20
21. ο Ganoxolone -
- Synthetic NS
- Positive allosteric modulator of GABAA receptors
- Only NS agent evaluated in human clinical trials for
Rx of epilepsy .
- Efficacious, well-tolerated & safe in partial seizures
(also infantile spasms.)
21
22. ο Cyclical occurrence of seizure exacerbations near the
time of menstruation or at other phases of the
menstrual cycle.
ο No specific drug therapy currently β limited success
with conventional antiepileptics.
ο β levels of Progesterone (or NS) - perimenstrual period
ο NS βreplacementβ β effective Rx
Synthetic NS (Ganoxolone) β more reliable than Prog
22
23. ο Cyclical symptoms β emotional & physical
ο PMDD β more severe form
ο Etio β unknown
ο Allopregnenolone β imp role
Levels β in luteal phase during PMS
ο BZDs Rx insensitive (d/t cross tolerance)
ο Natural Progesterones β no clear benefits
23
24. ο Evidence of NS involvement
ο NS β novel drugs for anxiety.
Allopregnanolone and THDOC - potent anxiolytics
Others β Progesterone, Sulfated NS
ο Produce anxiolytic effects without causing the side
effects normally associated with conventional
benzodiazepines (sedation and tolerance)
24
25. ο NS have a crucial role.
ο Fluoxetine (SSRI) β brain levels of Allopregnanolone
(direct activation of 3Ξ±-HSOR)
ο Depressed patients - plasma and cerebrospinal fluid
allopregnanolone levels are β
Can be normalized by effective Rx with fluoxetine .
ο Sulfated neurosteroids (PS and DHEAS) & DHEA β
clear antidepressant effects in animals and humans
25
26. 26
Several synthetic NS been used as sedatives for general
anaesthesia in surgical procedures.
β’ Hydroxydione
β 1st to be introduced
- useful anaesthetic drug with good safety profile
- was painful and irritating when injected.
β
β’ Althesin
- a mixture of alphaxolone and alphadolone.
- withdrawn from human use due to serious toxic
reactions,
- still used in veterinary medicine.
27. ο Minaxolone
- newer drug
- 3 times more potent than althesin
& retains the favourable safety profile.
- this drug was also ultimately withdrawn,
because animal studies suggested potential
carcinogenicity.
27
28. ο NS widely recognized to modulate learning and
memory processes in young, aged and in animal
models of amnesia
ο Normal aging and cognitive dysfunction is associated
with β levels of DHEA and DHEAS.
ο DHEA and DHEAS concentration found to be β in
Alzheimerβs patients.
28
29. ο In preclinical studies β
PS, DHEAS, & DHEA dose-dependently attenuated
memory deficits in aged mice,
(induced by the beta-amyloid Ξ²25β35 related to
Alzheimerβs disease)
ο Pregnenolone Rx β
as adjunctive for cognitive and negative symptoms
in patients with schizophrenia has been
investigated
29
30. ο NS play an important role in the alcohol tolerance and
withdrawal
ο Allopregnanolone
ο alters alcohol drinking behaviors in rodents.
ο These effects are a/w β in the sensitivity of GABA-A
receptors to NS
30
31. ο Sex difference in susceptibility to brain disorders
- long-standing issue in neuroscience research.
ο Anxiety and depression: Women > men.
ο Epilepsy:
incidence - Males > females.
31
32. ο Progesterone & testosterone β
key role in the gender-related differences in neural
excitability & susceptibility to seizures.
Precise mechanism is obscure.
ο Studies suggest - gender-specific distribution of
steroid hormones
32
33. ο Female mice exhibit significantly β sensitivity to
protective activity of allopregnanolone as compared
to males.
ο In Pilocarpine seizure test:
Androstanediol has similar β potency in
female mice
ο Significant sex differences in responses to NS
also evident during alcohol withdrawal.
33
34. ο NS are endogenous modulators of neural excitability.
ο Pharmacological effects d/t allosteric potentiation of
ππππ π receptors.
ο Evidence suggests endogenous role for NS in various
neurological and psychiatric conditions.
34
35. ο NS biosynthesis in brain - better understood,
but regulatory mechanisms not well characterized.
ο Hormonal influence on brain function in females
(puberty, menstrual cycle and menopause)
- more to be learned.
ο Role of NS in gender-specific brain conditions
- deserves further investigations.
35
36. ο The main challenge in NS research:
lack of specific antagonist(s) for NS sites on
ππππ π receptors.
ο Further studies clearly warranted β
to establish the molecular mechanisms of NS actions
& their impact on the human brain.
36
Neuroinflammation represents a common feature of many CNS pathologies, ranging from neurodegenerative to psychiatric diseases. Implicated both in onset & progression of the disease. Can disturb CNS function leading nerve dysfunction, degeneration & death. Thus, the possibility to modulate this phenomenon becomes valuable in terms of preventing disease progression.
The nervous system is a well-known target for the endocrine effects of hormonal steroids coming from peripheral steroidogenic glands. However, the nervous system is also controlled in a paracrine and autocrine manner by steroids directly synthesized by neurons and glial cells, named neurosteroids (Baulieu 1998). More recently, this concept was expanded into the neuroactive steroid family, including hormonal steroids, neurosteroids, and synthetic steroids that are able to regulate several neuronal functions
It is also known as neuroactive steroids.
It is define as the steroids which are synthesized from brain that act by rapidly alterΒ neuronal excitability through interaction withΒ ligand-gated ion channels Β and otherΒ cell surface receptors.
In brain it is synthesized in glial cells.
The termΒ neurosteroidΒ was coined by the FrenchΒ physiologistΒ Γtienne-Γmile BaulieuΒ and refers to steroids synthesized in the brain.[3][4]Β The term,Β neuroactive steroidΒ refers to steroids that can be synthesized in brain or are synthesized by an endocrine gland that then reach the brain through the bloodstream and have effects on brain function
(adrenals,gonads,and periphery tissues)
The term βneurosteroidsβ, originally coined by the French physiologist Etienne Baulieu.
Β term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy.
Neurosteroids have a wide range of potential clinical applications fromΒ sedationΒ to treatment ofΒ epilepsy[6]Β andΒ traumatic brain injury
Classification β
Based on differences inΒ activityΒ andΒ structure:
1. Inhibitory neurosteroids
2.Excitatory neurosteroids
3. Pheromones
Inhibitory neurosteroids[edit]
These neurosteroids exertΒ inhibitoryΒ actions onΒ neurotransmission. They act asΒ positive allosteric modulatorsΒ of theΒ GABAAΒ receptor(especiallyΒ Ξ΄ subunit-containingΒ isoforms), and possess, in no particular order,Β antidepressant,Β anxiolytic,Β stress-reducing,Β rewarding,[10]prosocial,[11]Β antiaggressive,[12]Β prosexual,[11]Β sedative,Β pro-sleep,[13]Β cognitiveΒ andΒ memory-impairing,[citation needed]Β analgesic,[14]anesthetic,Β anticonvulsant,Β neuroprotective, andΒ neurogenicΒ effects.[3]
Major examples include theΒ pregnanesΒ allopregnanoloneΒ (brexanolone),Β pregnanoloneΒ (eltanolone), andΒ tetrahydrodeoxycorticosterone(THDOC), theΒ androstaneΒ 3Ξ±-androstanediol, and theΒ cholestaneΒ cholesterol.
Excitatory neurosteroids[edit]
These neurosteroids haveΒ excitatoryΒ effects on neurotransmission. They act as potentΒ negative allosteric modulatorsΒ of the GABAAreceptor, weak positive allosteric modulators of theΒ NMDA receptor, and/orΒ agonistsΒ of theΒ Ο1Β receptor, and mostly haveΒ antidepressant,Β anxiogenic,Β cognitiveΒ andΒ memory-enhancing,Β convulsant,Β neuroprotective, andΒ neurogenicΒ effects.[3]
Major examples include the pregnanesΒ pregnenolone sulfateΒ (PS),Β epipregnanolone, andΒ isopregnanoloneΒ (sepranolone), the androstanesΒ dehydroepiandrosteroneΒ (DHEA;Β prasterone), andΒ dehydroepiandrosterone sulfateΒ (DHEA-S;Β prasterone sulfate), and the cholestaneΒ 24(S)-hydroxycholesterolΒ (NMDA receptor-selective; very potent)
Pheromones[edit]
Pheromones are neurosteroids that influence brain activity, notablyΒ hypothalamicΒ function, via activation ofΒ vomeronasal receptorcells.[18][19][20]
They include the androstanesΒ androstadienol,Β androstadienone,Β androstenol, andΒ androstenoneΒ and the estraneΒ estratetraenol.
Other neurosteroids[edit]
Certain other endogenous steroids, such asΒ pregnenolone,[21]Β progesterone,[22][23]Β estradiol,[5]Β andΒ corticosteroneΒ are also neurosteroids. However, unlike those listed above, these neurosteroids do not modulate the GABAAΒ or NMDA receptors, and instead affect various other cell surface receptors and non-genomic targets. Also, many endogenous steroids, including pregnenolone, progesterone, corticosterone,Β deoxycorticosterone, DHEA, andΒ testosterone, areΒ metabolizedΒ into (other) neurosteroids, effectively functioning as so-calledΒ proneurosteroids.
Biosynthesis
Neurosteroids are synthesized mainly fromΒ cholesterol,Β *Neurosteroidogenesis occurs in the brain regions such as cortex, hippocampus, and amygdala.
NS are A-ring reduced metabolites of the steroid hormones progesterone, deoxycorticosterone and testosterone (Fig.1). The steroid precursors of neurosteroids are mainly synthesized in the gonads, adrenal gland, and feto-placental unit. Several neurosteroids including allopregnanolone, THDOC, and androstanediol are generated by sequential reduction of the parent steroid by 5Ξ±-reductase and 3Ξ±-hydroxysteroid oxidoreductase (3Ξ±-HSOR) (Fig. 2). These conversion steps occur in peripheral tissues such as reproductive endocrine tissues, liver, and skin that are rich in the two reducing activities. steroid 5Ξ±-reduction is the rate-limiting step in the biosynthesis of neurosteroids. These Steroid precursors readily enter the brain so that pools of peripherally synthesized precursors are readily available for local neurosteroid biosynthesis.Β
The emerging evidence support that neurosteroid biosynthetic enzymes are present in the human brain (both neurons and glial cells) Thus, it is likely that neurosteroids can be formed from their parent hormonal steroids directly in the target brain region
Β The biosynthesis of neurosteroids is controlled by the translocator protein (18 kD), The translocator protein is widely found in the peripheral tissues and in the brain. It is mainly located in the outer mitochondrial membrane and favors the transport of cholesterol to the inner mitochondrial membrane, ultimately promoting neurosteroid synthesisΒ
Mechanisms of neurosteroid actions
neurosteroids are not themselves active at intracellular steroid receptors. They modulate brain excitability primarily by interaction with neuronal membrane receptors and ligand-gated ion channelsΒ ; most notably GABA-A receptorsΒ
* our recent studies in progesterone receptor (PR) knockout mice conclusively demonstrate that the classical steroid receptor is not required for the sedative, anxiolytic, and anticonvulsant activity of progesterone and related neurosteroidsΒ
Modulation of GABA-A receptors
The GABA-A receptor is a major target of neurosteroids (Fig.3). Neurosteroids can be positive or negative regulators of GABA-A receptor function, depending on the chemical structure of the steroid molecule.
There are two types of inhibitory neurotransmission mediated via GABA-A receptors: synaptic (phasic) and extrasynaptic (tonic) inhibition. Neurosteroids modulate both synaptic and extrasynaptic GABA-A receptors, and thereby potentiate both phasic and tonic currents.
The modulating effects of neurosteroids occur by binding to discrete sites on the GABA-A receptor that are located within the transmembrane domains of the Ξ±- and Ξ²-subunits; distinct from that of the GABA, benzodiazepine and barbiturate sites. Although the exact location of neurosteroid binding site is currently unknown,
Neurosteroid potentiation of GABA-A receptor-mediated currents
*Neurosteroids such as allopregnanolone, THDOC, and androstanediol are potent positive allosteric modulators of GABA-A receptors
neurosteroids greatly enhance the probability of GABA-A receptor chloride channel opening that allows massive chloride ion influx, thereby promoting augmentation of inhibitory GABAergic transmission.Β
*GABA-A receptors that contain the Ξ΄ subunit are more sensitive to neurosteroid-induced potentiation of GABA responses
At high concentrations (>10 ΞΌM), neurosteroids can directlyactivate GABA-A receptor channels in the absence of GABAΒ
These direct actions, have pharmacological significance with exogenously administered neurosteroids,
Modulation of glutamate and other neurotransmitter receptors
Some neurosteroids can modulate the N-methyl-D-apartate (NMDA) type glutamate receptors. Sulfated neurosteroids PS and DHEAS have been shown to be potent allosteric agonists at NMDA receptor complex (Wu et al., 1991). Generally, high micromolar concentrations of PS and DHEAS are necessaryΒ
Binding and pharmacological studies revealed that neurosteroids such as pregnenolone, DHEAS, and PS interact with Ο receptors, a distinct family of receptors present in high density in the brain. DHEAS and PS behaving as agonists and progesterone as an antagonist.
Physiological and pharmacological effects and therapeutic potentials
The physiological and pharmacological profile of major neurosteroids is listed inΒ Table 1. In general, neurosteroids that are 3Ξ±-hydroxy-pregnane derivatives such as allopregnanolone, pregnanolone, and THDOC elicit sedative, anxiolytic, and anticonvulsant actions (Reddy, 2003). PS and DHEAS are excitatory and produce memory enhancing and anxiogenic effects.
Synthetic neurosteroids that show better pharmacokinetics and efficacy are evaluated for sedative and anxiolytic (minaxolone), anesthetic (alphaxolone) and antiepileptic (ganaxolone) effects (Table 2).
Epilepsy
Neurosteroids are broad-spectrum anticonvulsant agents. They protect against seizures induced in animals.
Neurosteroids are highly effective in the pentylenetetrazol (PTZ) model of epilepsy.Β
The protective index (TD50/ED50Β values) of neurosteroids is comparable to those of clinically used antiepileptic drugs.
The sulfated neurosteroids PS and DHEAS are proconvulsants partly because they block GABA-A receptors and facilitate NMDA receptor functions.
Studies have shown that Synthetic neurosteroids, which are devoid of such hormonal actions, could provide a rational alternative approach to therapy.
Ganoxolone, a syn ns,
is a positive allosteric modulator of GABA-A receptors and is an effective anticonvulsant in the PTZ seizure test as well as in other anticonvulsant screening modelsΒ
Ganaxolone is the only neurosteroid-like agent that has been evaluated in human clinical trials for the treatment of epilepsyΒ . Overall, ganaxolone appears to be an efficacious, well-tolerated and safe treatment for partial seizures that is probably also effective for infantile spasms.
Catamenial epilepsy
Catamenial epilepsy, the cyclical occurrence of seizure exacerbations near the time of menstruation or at other phases of the menstrual cycle, affects a high proportion of women of reproductive age with drug refractory epilepsy.
Currently, there is no specific drug therapy for catamenial epilepsy;
Because progesterone is a powerful anticonvulsant hormone, decreasing levels of progesterone (or neurosteroids) during the perimenstrual period could result in catamenial seizure exacerbation.Β
Conventional antiepileptic drugs are used in catamenial epilepsy therapy. However, catamenial seizures are often not successfully treated with these drugs.Β
neurosteroid βreplacementβ as an effective therapy for catamenial epilepsy. Progesterone supplementation has been shown to reduce catamenial seizure frequency in women with epilepsy. may be associated with undesired hormonal side effects. Neurosteroids and synthetic analogs such as ganaxolone might provide an effective approach for catamenial epilepsy therapy that is more reliable and does not expose patients to the risk of hormonal side effectsΒ
Premenstrual syndrome
Premenstrual syndrome (PMS) is a chronic, cyclical disorder manifested by emotional and physical symptoms in the second half of the menstrual cycle. Premenstrual dysphoric disorder (PMDD) is more severe than PMS, with women reporting severe psychological symptoms of depression, anxiety, and mood swings, in addition to the more common complaints of bloating and breast pain. The etiology of PMS is unknown.Β
In normal women, allopregnanolone varies very similarly to progesterone throughout the menstrual cycle. Serum concentrations of the progesterone metabolite allopregnanolone during the luteal phase are lower in women with PMS. Thus, allopregnanolone could play an important role in the pathophysiology of PMS.
There is a marked insensitivity to benzodiazepine therapy in patients with PMS (Sundstrom et al., 1997), which might be due to the development of cross-tolerance between benzodiazepines and neurosteroid. Although neurosteroids represent promising approach for PMS, natural progesterone supplementation in women with PMS has no clear beneficial effectΒ
Anxiety
There is considerable evidence for an involvement of neurosteroids in the etiology of anxiety disorders.Β Neurosteroidogenic compounds might represent novel drugs for anxiety.
Neurosteroids such as allopregnanolone and THDOC are potent anxiolytic agents.
Others β P, Sulfated NS
These agents are proposed to produce anxiolytic effects without causing the side effects normally associated with conventional benzodiazepines such as sedation and tolerance.
Depression
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 through direct activation of 3Ξ±-HSOR, a critical enzyme in the synthesis of 3Ξ±-reduced neurosteroids. In depressed patients, plasma and cerebrospinal fluid allopregnanolone levels are reduced, can be normalized by clinically effective treatment with fluoxetineΒ .
Sulfated neurosteroids PS and DHEAS as well as DHEA have clear antidepressant effects in animals and humans
Anesthesia[edit]
Several synthetic neurosteroids have been used asΒ sedativesΒ for the purpose ofΒ general anaesthesiaΒ for carrying out surgical procedures.
The first of these to be introduced was hydroxydione, proved to be a useful anaesthetic drug with a good safety profile, but was painful and irritating when injected. This led to the development of newer neuroactive steroids.
The next drug from this family to be marketed was a mixture of alphaxolone and alphadolone, known asΒ Althesin. This was withdrawn from human use due to rare but serious toxic reactions, but is still used inΒ veterinary medicine.
The next neurosteroid anaesthetic introduced into human medicine was the newer drug minaxolone, which is around three times more potent than althesin and retains the favourable safety profile. Β However this drug was also ultimately withdrawn, not because of problems in clinical use, but because animal studies suggested potential carcinogenicity.
Learning and memory
Neurosteroids have been widely recognized to modulate learning and memory processes in young, aged and in pharmacological models of amnesiaΒ
Normal aging and cognitive dysfunction is associated with decreased levels of DHEA and DHEAS.
Β There is evidence that the concentrations of DHEA and DHEAS are decreased in patients suffering from Alzheimerβs disease
. Interestingly, DHEA is available in the market as an antiaging drug. In preclinical studies Β PS, DHEA, and DHEAS dose-dependently attenuated the memory deficits in aged mice, induced by the beta-amyloid Ξ²25β35 related to Alzheimerβs disease,
Pregnenolone treatment as adjunctive for cognitive and negative symptoms in patients with schizophrenia has been investigatedΒ
Alcohol withdrawal
Neurosteroids play an important role in the alcohol tolerance and withdrawalΒ
Allopregnanolone influences cognitive processing, spatial learning and memory and alters alcohol drinking behaviors in rodents.Β These effects are associated with increases in the sensitivity of GABA-A receptors to neurosteroids and suggest an important role in ethanol withdrawalΒ
Role of Neurosteroids in Sex Differences in Susceptibility to Brain Disorders
Sex difference in susceptibility to certain brain disorders is one of the long-standing issues in neuroscience research, both at the basic and clinical levels. Anxiety and depression affects more women than men.Β & also diff in therapeutic responses to antidepressants.
Whereas in c/o epilepsy, incidence is generally higher in males than in females.
Steroid hormones such as progesterone and testosterone play a key role in the gender-related differences in neural excitability & susceptibility to seizures. However, the precise mechanism underlying such sexual dimorphism is obscure.
Β Studies have suggested that 1 of the reasons for sex differences in seizure sensitivity are due to gender-specific distribution of steroid hormones
Both progesterone and allopregnanolone protects against experimental seizures in both male and female mice lacking progesterone receptors (Reddy et al., 2004).
However, female mice exhibit significantly enhanced sensitivity to the protective activity of allopregnanolone as compared to males. In the pilocarpine seizure test, androstanediol has similar increased potency in female mice, which is not related to differences in pharmacokinetics of this neurosteroid. Significant sex differences in responses to neurosteroids are also evident during alcohol withdrawal.
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.
Pathways of neurosteroid biosynthesis in the brain are better understood, but regulatory mechanisms are not well characterized.
Much has been learned about the hormonal influence on brain function in females during puberty, menstrual cycle and menopause, but there is much more that is yet to be learned.Β
The role of neurosteroids in gender-specific brain conditions certainly deserves further investigations.
Neurosteroid-based treatments are being developed for gender-specific conditions such as catamenial epilepsy. The main challenge in neurosteroid research is lack of specific antagonist(s) for neurosteroid sites on GABA-A receptors. Further studies are, therefore, clearly warranted to establish the molecular mechanisms of neurosteroid actions and their impact on the human brain.