Neuroactive steroid

Neuroactive steroids (or neurosteroids) rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels.^[1][2] In addition, these steroids may also exert effects on gene expression via intracellular steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy^[3] and traumatic brain injury.^[4][5] Ganaxolone, an analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy. ^[6]

Biosynthesis

Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids or gonadal steroids, especially testosterone. Neurosteroids are synthesized in the central and peripheral nervous system, especially in myelinating glial cells, from cholesterol or steroidal precursors imported from peripheral sources.^[7][8] They include 3β-hydroxy-Δ5 derivatives, such as pregnenolone (PREG) and dehydroepiandrosterone (DHEA), their sulfates, and reduced metabolites such as the tetrahydroderivative of progesterone 3α-hydroxy-5α-pregnane-20-one (3α,5α-THPROG).

Mechanism

These compounds can act as allosteric modulators of neurotransmitter receptors, such as GABA_A,^{[9][10][11][12]} NMDA,^[13] and sigma receptors.^[14] Progesterone (PROG) is also a neurosteroid which activates progesterone receptors expressed in peripheral and central glial cells.^{[15][16][17][18]} The 3α-hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone have been surmised to enhance GABA-mediated chloride currents, whereas pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate display functional antagonistic properties at GABA_A receptors.

Therapeutic application

Several synthetic neurosteroids have been used as sedatives for the purpose of general anaesthesia for carrying out surgical procedures. The best known of these are alphaxolone, alphadolone, hydroxydione and minaxolone. 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 as Althesin. This was withdrawn from human use due to rare but serious toxic reactions, but is still used in veterinary medicine.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, 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 neurosteroid ganaxolone, an analog of the progesterone metabolite allopregnanolone, has been extensively investigated in animal models and is currently in clinical trials for the treatment of epilepsy.^[19] Neurosteroids, including ganaxolone have a broad spectrum of activity in animal models.^[20] They may have advantages over other GABA_A receptor modulators, notably benzodiazepines, in that tolerance does not appear to occur with extended use.^[21][22] In clinical trials, ganaxolone was effective in the treatment of partial seizures in adults and was tolerated.^[6]

Role in antidepressant action

Certain antidepressant drugs such as fluoxetine and fluvoxamine which are generally thought to act primarily as selective serotonin reuptake inhibitors have also been found to increase the levels of certain neurosteroids.^[23][24] Based on these studies, it has been proposed that increased levels of neurosteroids induced by fluoxetine or fluvoxamine may significantly contribute to or even be the predominant mechanism of action of these antidepressant drugs.

Benzodiazepine effects on neurosteroids

Benzodiazepines may influence neurosteroid metabolism by virtue of their actions on translocator protein (TSPO; "peripheral benzodiazepine receptor")^[25]. The pharmacological actions of benzodiazepines at the GABA_A receptor are similar to those of neurosteroids. 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.^[26]

Antagonists

• 17-Phenylandrostenol - blocks the effects of neuroactive steroids without affecting responses produced by benzodiazepines or barbiturates

See also

• 5-alpha reductase
• GABA A receptor

References

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Further reading

• Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S (2005). "Neurosteroid access to the GABA_A receptor". J. Neurosci. 25 (50): 11605–13. doi:10.1523/JNEUROSCI.4173-05.2005. PMID 16354918. 
• Wang JM, Johnston PB, Ball BG, Brinton RD (2005). "The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression". J. Neurosci. 25 (19): 4706–18. doi:10.1523/JNEUROSCI.4520-04.2005. PMID 15888646. 
• Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, Watanabe H, Costa E, Guidotti A (2001). "Brain 5α-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation". Proc. Natl. Acad. Sci. U.S.A. 98 (5): 2849–54. doi:10.1073/pnas.051628598. PMC 30228. PMID 11226329. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=30228. 
• Melcangi RC, Celotti F, Martini L (1994). "Progesterone 5-alpha-reduction in neuronal and in different types of glial cell cultures: type 1 and 2 astrocytes and oligodendrocytes". Brain Res. 639 (2): 202–6. doi:10.1016/0006-8993(94)91731-0. PMID 8205473. 
• Corpéchot C, Robel P, Axelson M, Sjövall J, Baulieu EE (1981). "Characterization and measurement of dehydroepiandrosterone sulfate in rat brain". Proc. Natl. Acad. Sci. U.S.A. 78 (8): 4704–7. doi:10.1073/pnas.78.8.4704. PMC 320231. PMID 6458035. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=320231. </ref>