Neurosteroids, also known asneuroactive steroids, areendogenous or exogenoussteroids that rapidly alterneuronal excitability through interaction withligand-gated ion channels and othercell surface receptors.^[1][2] The termneurosteroid was coined by the FrenchphysiologistÉtienne-Émile Baulieu and refers to steroids synthesized in the brain.^[3][4] The term,neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by anendocrine gland, that then reach the brain through the bloodstream and have effects on brain function.^[5] The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects ongene expression via nuclearsteroid hormone receptors. Neurosteroids have a wide range of potential clinical applications fromsedation to treatment ofepilepsy^[6] andtraumatic brain injury.^[7][8]Ganaxolone, a synthetic analog of the endogenous neurosteroidallopregnanolone, is under investigation for the treatment of epilepsy.^[9]

Based on differences inactivity andstructure, neurosteroids can be broadly categorized into several different major groupings.^[3]

These neurosteroids exertinhibitory actions onneurotransmission. They act aspositive allosteric modulators of theGABA_A receptor (especiallyδ subunit-containingisoforms), and possess, in no particular order,antidepressant,anxiolytic,stress-reducing,rewarding,^[10]prosocial,^[11]antiaggressive,^[12]prosexual,^[11]sedative,pro-sleep,^[13]cognitive andmemory-impairing,^{[citation needed]}analgesic,^[14]anesthetic,anticonvulsant,neuroprotective, andneurogenic effects.^[3]

Major examples includetetrahydrodeoxycorticosterone (THDOC), theandrostane3α-androstanediol, thecholestanecholesterol and thepregnanespregnanolone (eltanolone),allopregnanolone (3α,5α-THP).^[15][16]

These neurosteroids haveexcitatory effects on neurotransmission. They act as potentnegative allosteric modulators of the GABA_A receptor, weak positive allosteric modulators of theNMDA receptor, and/oragonists of theσ₁ receptor, and mostly haveantidepressant,anxiogenic,cognitive andmemory-enhancing,convulsant,neuroprotective, andneurogenic effects.^[3]

Major examples include the pregnanespregnenolone sulfate (PS),epipregnanolone, andisopregnanolone (sepranolone), the androstanesdehydroepiandrosterone (DHEA;prasterone), anddehydroepiandrosterone sulfate (DHEA-S;prasterone sulfate), and the cholestane24(S)-hydroxycholesterol (NMDA receptor-selective; very potent).^[17]

Pheromones are neurosteroids that influence brain activity, notablyhypothalamic function, via activation ofvomeronasal receptorcells.^[18][19][20]

Possible human pheromones include the androstanesandrostadienol,androstadienone,androstenol, andandrostenone and the estraneestratetraenol.

Certain other endogenous steroids, such aspregnenolone,^[21]progesterone,^[22][23]estradiol,^[5] andcorticosterone are also neurosteroids. However, unlike those listed above, these neurosteroids do not modulate the GABA_A 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, andtestosterone, aremetabolized into (other) neurosteroids, effectively functioning as so-calledproneurosteroids.

Neurosteroids are synthesized fromcholesterol, which is converted into pregnenolone and then into all other endogenous steroids. Neurosteroids are produced in the brain after local synthesis or by conversion of peripherally-derivedadrenal steroids or gonadal steroids. They accumulate especially in myelinating glial cells, from cholesterol or steroidal precursors imported from peripheral sources.^[24][25]5α-reductase type I and3α-hydroxysteroid dehydrogenase are involved in the biosynthesis of inhibitory neurosteroids, while3β-hydroxysteroid dehydrogenase andhydroxysteroid sulfotransferases are involved in excitatory neurosteroid production.^[3]

Some major knownbiological functions of neurosteroids include modulation ofneural plasticity,^[26]learning andmemory processes,^[27]behavior,^[28][29] andseizure susceptibility,^[30] as well as responses tostress,anxiety, anddepression.^[11][31] Neurosteroids also appear to play an important role in varioussexually-dimorphic behaviors and emotional responses.^[29]

Acute stress elevates the levels of inhibitory neurosteroids like allopregnanolone, and these neurosteroids are known to counteract many of the effects of stress.^[32] This is similar to the case ofendorphins, which are released in response to stress and physical pain and counteract the negative subjective effects of such states. As such, it has been suggested that one of the biological functions of theseneuromodulators may be to help maintain emotionalhomeostasis.^[28][33]Chronic stress has been associated with diminished levels of allopregnanolone and altered allopregnanolone stress responsivity,psychiatric disorders, andhypothalamic-pituitary-adrenal axis dysregulation.^[31][32]

It is thought that fluctuations in the levels of inhibitory neurosteroids during themenstrual cycle andpregnancy play an important role in a variety ofwomen'sconditions, includingpremenstrual syndrome (PMS),premenstrual dysphoric disorder (PMDD),postpartum depression (PPD),postpartum psychosis, andcatamenial epilepsy.^[34][35][36] In addition, it is thought that changes in neurosteroid levels may be involved in the changes in mood, anxiety, and sexual desire that occur duringpuberty in both sexes and duringmenopause in women.^[3][37][38]

Elevated levels of inhibitory neurosteroids, namely allopregnanolone, can produce paradoxical effects, such asnegative mood,anxiety,irritability, andaggression.^{[39][40][41][42]} This appears to be because these neurosteroids, like other positive allosteric modulators of the GABA_A receptor such as thebenzodiazepines,barbiturates, andethanol,^[34][42] possess biphasic, U-shaped actions – moderate levels (in the range of 1.5–2 nM/L total alloprogesterone, which are approximately equivalent toluteal phase levels) inhibit the activity of the GABA_A receptor, while lower and higher concentrations facilitate the activity of the receptor.^[40][41]

Several synthetic neurosteroids have been used assedatives for the purpose ofgeneral anaesthesia for carrying out surgical procedures. The best known of these arealphaxolone,alphadolone,hydroxydione, andminaxolone. The first of these to be introduced was hydroxydione, which is the esterified 21-hydroxy derivative of 5β-pregnanedione. Hydroxydione proved to be a useful anaesthetic drug with a good safety profile, but was painful and irritating when injected probably due to poor water solubility. 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 asAlthesin. This was withdrawn from human use due to rare but serious toxic reactions, but is still used inveterinary 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, without the toxicity problems seen with althesin. However this drug was also ultimately withdrawn, not because of problems in clinical use, but because animal studies suggested potential carcinogenicity and since alternative agents were available it was felt that the possible risk outweighed the benefit of keeping the drug on the market.

The neurosteroidganaxolone, an analog of the progesterone metabolite allopregnanolone, has been extensively investigated in animal models and is currently in clinical trials for the treatment ofepilepsy. Neurosteroids, including ganaxolone have a broad spectrum of activity in animal models.^[46] They may have advantages over other GABA_A 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.

Researchers have suggested the use of so-called "neurosteroid replacement therapy" as a way of treatingcatamenial epilepsy with neuroactive steroids such as ganaxolone during the period of themenstrual cycle whenseizure frequency increases.^[6]Micronized progesterone, which behaves reliably as aprodrug to allopregnanolone, has been suggested as a treatment for catamenial epilepsy in the same manner.^[49]

Allopregnanolone (SAGE-547) is under development as anintravenous therapy for the treatment ofsuper-refractory status epilepticus,postpartum depression, andessential tremor.^[50]

4,16-Androstadien-3β-ol (PH94B, Aloradine) is a synthetic pheromone, orpherine, neurosteroid which is under investigation for the treatment ofanxiety disorders in women.^[19][20][51]

3β-Methoxypregnenolone (MAP-4343), or pregnenolone 3β-methyl ether, is a synthetic neuroactive steroid and pregnenolone derivative that interacts withmicrotubule-associated protein 2 (MAP2) in a similar manner to pregnenolone and is under development for potential clinical use for indications such as the treatment ofbrain andspinal cord injury anddepressive disorders.^{[52][53][54][55]}

Certainantidepressant drugs such asfluoxetine andfluvoxamine, which are generally thought to affect depression by acting asselective 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 thereuptake ofserotonin. This suggests that other actions involving neurosteroids may also be at play in the effectiveness of these drugs against depression.^[56][57]

The3α-hydroxysteroid dehydrogenase (3α-HSD) enzyme isinduced by certain (SSRIs), includingfluoxetine,fluvoxamine,sertraline, andparoxetine, as well as by certain otherantidepressants likevenlafaxine andmirtazapine, and these antidepressants have been found to increase inhibitory neurosteroid levels.^{[58][59][60][61]} Enhancement of biosynthesis of inhibitory neurosteroids has been implicated in theantidepressant andanxiolytic effects of some of the SSRIs.^[58]

Benzodiazepines may influence neurosteroid metabolism by virtue of their actions ontranslocator protein (TSPO; "peripheral benzodiazepine receptor").^[62] Thepharmacological actions of benzodiazepines at the GABA_A receptor are similar to those of neurosteroids, although the localization of benzodiazepine and neurosteroid-sensitive GABA_A receptor subtypes vary.^[63] Factors which affect the ability of individual benzodiazepines to alter neurosteroid levels may depend upon whether the individual benzodiazepine drug interacts with TSPO. Some benzodiazepines may also inhibit neurosteroidogenic enzymes reducing neurosteroid synthesis.^[64]

• List of neurosteroids
• Neurosteroidogenesis inhibitor
• Membrane steroid receptor

• Neurosteroids
• Neurophysiology

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