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1
 Introduction
 Definition
 Classification
 Biosynthesis
 Mechanisms of action
 Pharmacological actions
 Therapeutic implications
 Role in sex differences in susceptibility to brain
disorders
 Conclusion & future perspectives
2
 Neuroinflammation is a common feature of many CNS
pathologies - onset & progression
 nerve dysfunction, degeneration & death.
3
Hormonal
Steroids
Peripheral glands
Neuroactive
steroids
 aka Neuroactive steroids.
‘Steroids synthesized from brain that act by rapidly
altering neuronal excitability through interaction
with ligand-gated ion channels and other cell surface
receptors.’
Neurosteroids = Brain
Neuroactive steroids = Brain + Endocrine glands
(adrenals, gonads)
4
 ‘Neurosteroids’ originally coined by the French
physiologist Etienne Baulieu.
 ”Neuroactive steroids” was first coined in 1992 by
Steven Paul and Robert Purdy.
 Wide range of potential clinical applications
from sedation to treatment of epilepsy &
traumatic brain injury
5
1. Inhibitory neurosteroids
2. Excitatory neurosteroids
6
 Exert inhibitory actions on neurotransmission
 Positive allosteric modulators of 𝐆𝐀𝐁𝐀 𝐀receptor
 Antidepressant, anxiolytic, stress-reducing, sedative-
hypnotic, anaesthetic, anticonvulsant, cognitive and
neuroprotective effects.
 Eg. Allopregnanolone, Pregnanolone,
Tetrahydrodeoxycorticosterone (THDOC),
3α-androstanediol,
7
 Excitatory effects on neurotransmission.
 Potent negative allosteric modulators of 𝐆𝐀𝐁𝐀 𝐀 R,
weak positive modulators of NMDA R & agonists of
σ1 receptor.
 Antidepressant, anxiogenic, Cognitive & memory
enhancing, convulsant, etc
 Pregnenolone sulfate (PS), Dehydroepiandrosterone
(DHEA), Dehydroepiandrosterone sulfate (DHEA-S),
24(S) hydroxycholesterol
8
 Pheromones
Influence brain activity (hypothalamic function)
Eg. Androstenol & Androstenone
Estratetraenol
 Others –
Endogenous – Progesterone, Estradiol & Corticosterone
do not modulate the GABAA or NMDA receptors,
instead affect various other cell surface receptors
9

10
 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
 promotes neurosteroid synthesis
11
 Not active at intracellular steroid receptors.
 Interact with neuronal membrane receptors and
ligand-gated ion channels - 𝐆𝐀𝐁𝐀 𝐀 receptors
 Progesterone receptor (PR) knockout mice studies
demonstrate that –
Classical steroid receptor is not required for the
sedative, anxiolytic, & anticonvulsant activity of
progesterone & related NS
12
13
14
 𝐆𝐀𝐁𝐀 𝐀 receptor - major target
 Neurosteroids - Positive or Negative regulators
 2 types of inhibitory neurotransmission mediated via
GABA-A receptors:
- Synaptic (phasic) inhibition
- Extrasynaptic (tonic) inhibition.
Neurosteroids potentiate both phasic and tonic currents.
15
16
Neurosteroids
↓
↑ GABA-A receptor Cl- channel opening
↓
Massive Cl- ion influx
↓
promoting inhibitory GABAergic transmission.
• GABA-A receptors containing δ subunit - more
sensitive to NS
• At high concentrations (>10 μM), NS can directly
activate GABA-A receptor channels in the absence of
GABA
Modulation of glutamate and other
neurotransmitter receptors –
 NMDA-type glutamate receptors -
Sulfated NS ( PS & DHEAS) are potent allosteric
agonists
 σ receptors –
- Present in brain
- Agonists: PS & DHEAS
Antagonist: Progesterone
17
18
19
 Broad-spectrum anticonvulsant agents.
 Highly effective in the Pentylenetetrazol (PTZ) model
of epilepsy.
 Sulfated NS (PS and DHEAS) are proconvulsants
- block GABAA receptors and facilitate NMDA
receptor functions.
 Synthetic NS - rational alternative approach to
anti-convulsant therapy
20
 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
 Cyclical occurrence of seizure exacerbations near the
time of menstruation or at other phases of the
menstrual cycle.
 No specific drug therapy currently – limited success
with conventional antiepileptics.
 ↓ levels of Progesterone (or NS) - perimenstrual period
 NS “replacement” – effective Rx
Synthetic NS (Ganoxolone) – more reliable than Prog
22
 Cyclical symptoms – emotional & physical
 PMDD – more severe form
 Etio – unknown
 Allopregnenolone – imp role
Levels ↓ in luteal phase during PMS
 BZDs Rx insensitive (d/t cross tolerance)
 Natural Progesterones – no clear benefits
23
 Evidence of NS involvement
 NS – novel drugs for anxiety.
Allopregnanolone and THDOC - potent anxiolytics
Others – Progesterone, Sulfated NS
 Produce anxiolytic effects without causing the side
effects normally associated with conventional
benzodiazepines (sedation and tolerance)
24
 NS have a crucial role.
 Fluoxetine (SSRI) ↑ brain levels of Allopregnanolone
(direct activation of 3α-HSOR)
 Depressed patients - plasma and cerebrospinal fluid
allopregnanolone levels are ↓
Can be normalized by effective Rx with fluoxetine .
 Sulfated neurosteroids (PS and DHEAS) & DHEA –
clear antidepressant effects in animals and humans
25
26
Several synthetic NS been used as sedatives for general
anaesthesia in surgical procedures.
• Hydroxydione
– 1st to be introduced
- useful anaesthetic drug with good safety profile
- was painful and irritating when injected.
↓
• Althesin
- a mixture of alphaxolone and alphadolone.
- withdrawn from human use due to serious toxic
reactions,
- still used in veterinary medicine.
 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
 NS widely recognized to modulate learning and
memory processes in young, aged and in animal
models of amnesia
 Normal aging and cognitive dysfunction is associated
with ↓ levels of DHEA and DHEAS.
 DHEA and DHEAS concentration found to be ↓ in
Alzheimer’s patients.
28
 In preclinical studies –
PS, DHEAS, & DHEA dose-dependently attenuated
memory deficits in aged mice,
(induced by the beta-amyloid β25–35 related to
Alzheimer’s disease)
 Pregnenolone Rx –
as adjunctive for cognitive and negative symptoms
in patients with schizophrenia has been
investigated
29
 NS play an important role in the alcohol tolerance and
withdrawal
 Allopregnanolone
 alters alcohol drinking behaviors in rodents.
 These effects are a/w ↑ in the sensitivity of GABA-A
receptors to NS
30
 Sex difference in susceptibility to brain disorders
- long-standing issue in neuroscience research.
 Anxiety and depression: Women > men.
 Epilepsy:
incidence - Males > females.
31
 Progesterone & testosterone –
key role in the gender-related differences in neural
excitability & susceptibility to seizures.
Precise mechanism is obscure.
 Studies suggest - gender-specific distribution of
steroid hormones
32
 Female mice exhibit significantly ↑ sensitivity to
protective activity of allopregnanolone as compared
to males.
 In Pilocarpine seizure test:
Androstanediol has similar ↑ potency in
female mice
 Significant sex differences in responses to NS
also evident during alcohol withdrawal.
33
 NS are endogenous modulators of neural excitability.
 Pharmacological effects d/t allosteric potentiation of
𝐆𝐀𝐁𝐀 𝐀 receptors.
 Evidence suggests endogenous role for NS in various
neurological and psychiatric conditions.
34
 NS biosynthesis in brain - better understood,
but regulatory mechanisms not well characterized.
 Hormonal influence on brain function in females
(puberty, menstrual cycle and menopause)
- more to be learned.
 Role of NS in gender-specific brain conditions
- deserves further investigations.
35
 The main challenge in NS research:
lack of specific antagonist(s) for NS sites on
𝐆𝐀𝐁𝐀 𝐀 receptors.
 Further studies clearly warranted –
to establish the molecular mechanisms of NS actions
& their impact on the human brain.
36
1) Reddy DS. Neurosteroids: Endogenous Role in the
Human Brian and Therapeutic Potentials. Progress
in brain research. 2010;186:113-137.
doi:10.1016/B978-0-444-53630-3.00008-7.
2) Silvia Giatti et al. Neuroactive steroids, their
metabolites, and neuroinflammation. J Mol
Endocrinol. 2012;49:125-134
3) Mellédo, J.-M. L., & Baker, G. B. (2002).
Neuroactive steroids and anxiety disorders. Journal
of Psychiatry and Neuroscience, 27(3), 161–165.
37
1, 2012 49R125-R134

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Neuroactive steroids

  • 1. 1
  • 2.  Introduction  Definition  Classification  Biosynthesis  Mechanisms of action  Pharmacological actions  Therapeutic implications  Role in sex differences in susceptibility to brain disorders  Conclusion & future perspectives 2
  • 3.  Neuroinflammation is a common feature of many CNS pathologies - onset & progression  nerve dysfunction, degeneration & death. 3 Hormonal Steroids Peripheral glands Neuroactive steroids
  • 4.  aka Neuroactive steroids. ‘Steroids synthesized from brain that act by rapidly altering neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors.’ Neurosteroids = Brain Neuroactive steroids = Brain + Endocrine glands (adrenals, gonads) 4
  • 5.  ‘Neurosteroids’ originally coined by the French physiologist Etienne Baulieu.  ”Neuroactive steroids” was first coined in 1992 by Steven Paul and Robert Purdy.  Wide range of potential clinical applications from sedation to treatment of epilepsy & traumatic brain injury 5
  • 6. 1. Inhibitory neurosteroids 2. Excitatory neurosteroids 6
  • 7.  Exert inhibitory actions on neurotransmission  Positive allosteric modulators of 𝐆𝐀𝐁𝐀 𝐀receptor  Antidepressant, anxiolytic, stress-reducing, sedative- hypnotic, anaesthetic, anticonvulsant, cognitive and neuroprotective effects.  Eg. Allopregnanolone, Pregnanolone, Tetrahydrodeoxycorticosterone (THDOC), 3α-androstanediol, 7
  • 8.  Excitatory effects on neurotransmission.  Potent negative allosteric modulators of 𝐆𝐀𝐁𝐀 𝐀 R, weak positive modulators of NMDA R & agonists of σ1 receptor.  Antidepressant, anxiogenic, Cognitive & memory enhancing, convulsant, etc  Pregnenolone sulfate (PS), Dehydroepiandrosterone (DHEA), Dehydroepiandrosterone sulfate (DHEA-S), 24(S) hydroxycholesterol 8
  • 9.  Pheromones Influence brain activity (hypothalamic function) Eg. Androstenol & Androstenone Estratetraenol  Others – Endogenous – Progesterone, Estradiol & Corticosterone do not modulate the GABAA or NMDA receptors, instead affect various other cell surface receptors 9
  • 11.  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  promotes neurosteroid synthesis 11
  • 12.  Not active at intracellular steroid receptors.  Interact with neuronal membrane receptors and ligand-gated ion channels - 𝐆𝐀𝐁𝐀 𝐀 receptors  Progesterone receptor (PR) knockout mice studies demonstrate that – Classical steroid receptor is not required for the sedative, anxiolytic, & anticonvulsant activity of progesterone & related NS 12
  • 13. 13
  • 14. 14  𝐆𝐀𝐁𝐀 𝐀 receptor - major target  Neurosteroids - Positive or Negative regulators  2 types of inhibitory neurotransmission mediated via GABA-A receptors: - Synaptic (phasic) inhibition - Extrasynaptic (tonic) inhibition. Neurosteroids potentiate both phasic and tonic currents.
  • 15. 15
  • 16. 16 Neurosteroids ↓ ↑ GABA-A receptor Cl- channel opening ↓ Massive Cl- ion influx ↓ promoting inhibitory GABAergic transmission. • GABA-A receptors containing δ subunit - more sensitive to NS • At high concentrations (>10 μM), NS can directly activate GABA-A receptor channels in the absence of GABA
  • 17. Modulation of glutamate and other neurotransmitter receptors –  NMDA-type glutamate receptors - Sulfated NS ( PS & DHEAS) are potent allosteric agonists  σ receptors – - Present in brain - Agonists: PS & DHEAS Antagonist: Progesterone 17
  • 18. 18
  • 19. 19
  • 20.  Broad-spectrum anticonvulsant agents.  Highly effective in the Pentylenetetrazol (PTZ) model of epilepsy.  Sulfated NS (PS and DHEAS) are proconvulsants - block GABAA receptors and facilitate NMDA receptor functions.  Synthetic NS - rational alternative approach to anti-convulsant therapy 20
  • 21.  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.  Cyclical occurrence of seizure exacerbations near the time of menstruation or at other phases of the menstrual cycle.  No specific drug therapy currently – limited success with conventional antiepileptics.  ↓ levels of Progesterone (or NS) - perimenstrual period  NS “replacement” – effective Rx Synthetic NS (Ganoxolone) – more reliable than Prog 22
  • 23.  Cyclical symptoms – emotional & physical  PMDD – more severe form  Etio – unknown  Allopregnenolone – imp role Levels ↓ in luteal phase during PMS  BZDs Rx insensitive (d/t cross tolerance)  Natural Progesterones – no clear benefits 23
  • 24.  Evidence of NS involvement  NS – novel drugs for anxiety. Allopregnanolone and THDOC - potent anxiolytics Others – Progesterone, Sulfated NS  Produce anxiolytic effects without causing the side effects normally associated with conventional benzodiazepines (sedation and tolerance) 24
  • 25.  NS have a crucial role.  Fluoxetine (SSRI) ↑ brain levels of Allopregnanolone (direct activation of 3α-HSOR)  Depressed patients - plasma and cerebrospinal fluid allopregnanolone levels are ↓ Can be normalized by effective Rx with fluoxetine .  Sulfated neurosteroids (PS and DHEAS) & DHEA – clear antidepressant effects in animals and humans 25
  • 26. 26 Several synthetic NS been used as sedatives for general anaesthesia in surgical procedures. • Hydroxydione – 1st to be introduced - useful anaesthetic drug with good safety profile - was painful and irritating when injected. ↓ • Althesin - a mixture of alphaxolone and alphadolone. - withdrawn from human use due to serious toxic reactions, - still used in veterinary medicine.
  • 27.  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.  NS widely recognized to modulate learning and memory processes in young, aged and in animal models of amnesia  Normal aging and cognitive dysfunction is associated with ↓ levels of DHEA and DHEAS.  DHEA and DHEAS concentration found to be ↓ in Alzheimer’s patients. 28
  • 29.  In preclinical studies – PS, DHEAS, & DHEA dose-dependently attenuated memory deficits in aged mice, (induced by the beta-amyloid β25–35 related to Alzheimer’s disease)  Pregnenolone Rx – as adjunctive for cognitive and negative symptoms in patients with schizophrenia has been investigated 29
  • 30.  NS play an important role in the alcohol tolerance and withdrawal  Allopregnanolone  alters alcohol drinking behaviors in rodents.  These effects are a/w ↑ in the sensitivity of GABA-A receptors to NS 30
  • 31.  Sex difference in susceptibility to brain disorders - long-standing issue in neuroscience research.  Anxiety and depression: Women > men.  Epilepsy: incidence - Males > females. 31
  • 32.  Progesterone & testosterone – key role in the gender-related differences in neural excitability & susceptibility to seizures. Precise mechanism is obscure.  Studies suggest - gender-specific distribution of steroid hormones 32
  • 33.  Female mice exhibit significantly ↑ sensitivity to protective activity of allopregnanolone as compared to males.  In Pilocarpine seizure test: Androstanediol has similar ↑ potency in female mice  Significant sex differences in responses to NS also evident during alcohol withdrawal. 33
  • 34.  NS are endogenous modulators of neural excitability.  Pharmacological effects d/t allosteric potentiation of 𝐆𝐀𝐁𝐀 𝐀 receptors.  Evidence suggests endogenous role for NS in various neurological and psychiatric conditions. 34
  • 35.  NS biosynthesis in brain - better understood, but regulatory mechanisms not well characterized.  Hormonal influence on brain function in females (puberty, menstrual cycle and menopause) - more to be learned.  Role of NS in gender-specific brain conditions - deserves further investigations. 35
  • 36.  The main challenge in NS research: lack of specific antagonist(s) for NS sites on 𝐆𝐀𝐁𝐀 𝐀 receptors.  Further studies clearly warranted – to establish the molecular mechanisms of NS actions & their impact on the human brain. 36
  • 37. 1) Reddy DS. Neurosteroids: Endogenous Role in the Human Brian and Therapeutic Potentials. Progress in brain research. 2010;186:113-137. doi:10.1016/B978-0-444-53630-3.00008-7. 2) Silvia Giatti et al. Neuroactive steroids, their metabolites, and neuroinflammation. J Mol Endocrinol. 2012;49:125-134 3) Mellédo, J.-M. L., & Baker, G. B. (2002). Neuroactive steroids and anxiety disorders. Journal of Psychiatry and Neuroscience, 27(3), 161–165. 37 1, 2012 49R125-R134

Editor's Notes

  1. 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
  2. It is also known as neuroactive steroids. It is define as the steroids which are synthesized from brain that act by rapidly alter neuronal excitability through interaction with ligand-gated ion channels  and other cell surface receptors. In brain it is synthesized in glial cells. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain.[3][4] The term, neuroactive steroid 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)
  3. The term ‘neurosteroids’, originally coined by the French physiologist Etienne Baulieu.  term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy[6] and traumatic brain injury
  4. Classification – Based on differences in activity and structure: 1. Inhibitory neurosteroids 2.Excitatory neurosteroids 3. Pheromones
  5. Inhibitory neurosteroids[edit] These neurosteroids exert inhibitory actions on neurotransmission. They act as positive allosteric modulators of the GABAA receptor(especially δ subunit-containing isoforms), and possess, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,[10]prosocial,[11] antiaggressive,[12] prosexual,[11] sedative, pro-sleep,[13] cognitive and memory-impairing,[citation needed] analgesic,[14]anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.[3] Major examples include the pregnanes allopregnanolone (brexanolone), pregnanolone (eltanolone), and tetrahydrodeoxycorticosterone(THDOC), the androstane 3α-androstanediol, and the cholestane cholesterol.
  6. Excitatory neurosteroids[edit] These neurosteroids have excitatory effects on neurotransmission. They act as potent negative allosteric modulators of the GABAAreceptor, weak positive allosteric modulators of the NMDA receptor, and/or agonists of the σ1 receptor, and mostly have antidepressant, anxiogenic, cognitive and memory-enhancing, convulsant, neuroprotective, and neurogenic effects.[3] Major examples include the pregnanes pregnenolone sulfate (PS), epipregnanolone, and isopregnanolone (sepranolone), the androstanes dehydroepiandrosterone (DHEA; prasterone), and dehydroepiandrosterone sulfate (DHEA-S; prasterone sulfate), and the cholestane 24(S)-hydroxycholesterol (NMDA receptor-selective; very potent)
  7. Pheromones[edit] Pheromones are neurosteroids that influence brain activity, notably hypothalamic function, via activation of vomeronasal receptorcells.[18][19][20] They include the androstanes androstadienol, androstadienone, androstenol, and androstenone and the estrane estratetraenol. Other neurosteroids[edit] 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.
  8. Biosynthesis Neurosteroids are synthesized mainly from cholesterol, *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 5α-reductase and 3α-hydroxysteroid oxidoreductase (3α-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 5α-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.  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
  9.  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 synthesis 
  10. 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 channels ; most notably GABA-A receptors  * 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 neurosteroids 
  11. 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.
  12. 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 α- and β-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
  13. 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.  *GABA-A receptors that contain the δ subunit are more sensitive to neurosteroid-induced potentiation of GABA responses At high concentrations (>10 μM), neurosteroids can directlyactivate GABA-A receptor channels in the absence of GABA  These direct actions, have pharmacological significance with exogenously administered neurosteroids,
  14. 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 necessary  Binding and pharmacological studies revealed that neurosteroids such as pregnenolone, DHEAS, and PS interact with σ receptors, a distinct family of receptors present in high density in the brain. DHEAS and PS behaving as agonists and progesterone as an antagonist.
  15. 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 elicit sedative, anxiolytic, and anticonvulsant actions (Reddy, 2003). PS and DHEAS are excitatory and produce memory enhancing and anxiogenic effects.
  16. Synthetic neurosteroids that show better pharmacokinetics and efficacy are evaluated for sedative and anxiolytic (minaxolone), anesthetic (alphaxolone) and antiepileptic (ganaxolone) effects (Table 2).
  17. 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.  The protective index (TD50/ED50 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.
  18. 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 models  Ganaxolone is the only neurosteroid-like agent that has been evaluated in human clinical trials for the treatment of epilepsy . Overall, ganaxolone appears to be an efficacious, well-tolerated and safe treatment for partial seizures that is probably also effective for infantile spasms.
  19. 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.  Conventional antiepileptic drugs are used in catamenial epilepsy therapy. However, catamenial seizures are often not successfully treated with these drugs.  neurosteroid “replacement” 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 effects 
  20. 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.  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 effect 
  21. Anxiety There is considerable evidence for an involvement of neurosteroids in the etiology of anxiety disorders. Neurosteroidogenic compounds might represent novel drugs for anxiety. Neurosteroids such as allopregnanolone and THDOC are potent anxiolytic agents. Others – 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.
  22. 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 3α-HSOR, a critical enzyme in the synthesis of 3α-reduced neurosteroids. In depressed patients, plasma and cerebrospinal fluid allopregnanolone levels are reduced, can be normalized by clinically effective treatment with fluoxetine . Sulfated neurosteroids PS and DHEAS as well as DHEA have clear antidepressant effects in animals and humans
  23. Anesthesia[edit] Several synthetic neurosteroids have been used as sedatives for the purpose of general anaesthesia 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 as Althesin. This was withdrawn from human use due to rare but serious toxic reactions, but is still used in veterinary medicine.
  24. 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.  However this drug was also ultimately withdrawn, not because of problems in clinical use, but because animal studies suggested potential carcinogenicity.
  25. Learning and memory Neurosteroids have been widely recognized to modulate learning and memory processes in young, aged and in pharmacological models of amnesia  Normal aging and cognitive dysfunction is associated with decreased levels of DHEA and DHEAS.  There is evidence that the concentrations of DHEA and DHEAS are decreased in patients suffering from Alzheimer’s disease
  26. . Interestingly, DHEA is available in the market as an antiaging drug. In preclinical studies  PS, DHEA, and DHEAS dose-dependently attenuated the memory deficits in aged mice, induced by the beta-amyloid β25–35 related to Alzheimer’s disease, Pregnenolone treatment as adjunctive for cognitive and negative symptoms in patients with schizophrenia has been investigated 
  27. Alcohol withdrawal Neurosteroids play an important role in the alcohol tolerance and withdrawal  Allopregnanolone influences cognitive processing, spatial learning and memory and alters alcohol drinking behaviors in rodents. These effects are associated with increases in the sensitivity of GABA-A receptors to neurosteroids and suggest an important role in ethanol withdrawal 
  28. 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. & also diff in therapeutic responses to antidepressants. Whereas in c/o epilepsy, incidence is generally higher in males than in females.
  29. 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.  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).
  30. 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.
  31. 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.
  32. 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.  The role of neurosteroids in gender-specific brain conditions certainly deserves further investigations.
  33. 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.