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.

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
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3.  Neuroinflammation is a common feature of many CNS
pathologies - onset & progression
 nerve dysfunction, degeneration & death.
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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)
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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
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6. 1. Inhibitory neurosteroids
2. Excitatory neurosteroids
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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,
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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
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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
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10. 
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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
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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
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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
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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
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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.)
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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
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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
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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)
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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
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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.
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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.
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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
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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
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31.  Sex difference in susceptibility to brain disorders
- long-standing issue in neuroscience research.
 Anxiety and depression: Women > men.
 Epilepsy:
incidence - Males > females.
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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
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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.
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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.
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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.
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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.
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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.
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