Neuroactive steroids

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Neuroactive steroids (or neurosteroids) rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. In addition, these steroids may also exert effects on gene expression via intracellular steroid hormone receptors. Neurosteroids have a wide range of applications from sedation to treatment of epilepsy and traumatic brain injury.

Apart from exerting effects on the genome via intracellular steroid receptors, neuroactive steroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids. The 3alpha-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.

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. 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, NMDA, and sigma receptors. Progesterone (PROG) is also a neurosteroid which activates progesterone receptors expressed in peripheral and central glial cells. 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.

More recently, another neurosteroid ganaxolone has been developed and is currently in clinical trials for the treatment of epilepsy. This drug has less sedative effects than the anaesthetic neurosteroids listed above, but is a potent anticonvulsant which may have some advantages over older anticonvulsant drugs, mainly less development of tolerance with extended use.

Role in antidepressant action

Certain antidepressant drugs such as fluoxetine and fluvoxamine which were thought to act primarily as selective serotonin reuptake inhibitors have also been found to increase the levels of certain neurosteroids. 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 predominate mechanism of action of these antidepressant drugs.

Benzodiazepines and effect on neurosteroids

Benzodiazepines may influence neurosteroid metabolism and progesterone levels which in turn may influence the functions of the brain. The pharmacological actions of benzodiazepines at the GABA_A receptor are similar to those of neurosteroids. Neuroactive steroids are positive allosteric modulators of the GABA_A receptor, enhancing GABA function. Many benzodiazepines (diazepam, medazepam, estazolam, nitrazepam flunitrazepam and temazepam) potently inhibit the enzymes involved in the metabolism of neurosteroids. Long-term administration of benzodiazepines may influence the concentrations of endogenous neurosteroids, and thereby would modulate the emotional state. Factors which effects the ability of individual benzodiazepines to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine drug. Presence of a substituent at N1 position of the diazepine ring and/or the chloro or nitro group at position 7 of the benzene ring contribute to potent inhibition of the isoenzymes, and in turn a bromo group at position 7 (for bromazepam) and additional substituents (3-hydroxy group for oxazepam and tetrahydroxazole ring for cloxazolam and oxazolam) decrease the inhibitory potency of benzodiazepines on neurosteroids.

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

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.
• 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.
• Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, Watanabe H, Costa E, Guidotti A (2001). Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc. Natl. Acad. Sci. U.S.A. 98 (5): 2849–54.
• 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.
• 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.</ref>

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External links

• A clinical research study