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Individual differences |
Methods | Statistics | Clinical | Educational | Industrial | Professional items | World psychology |
Biological: Behavioural genetics · Evolutionary psychology · Neuroanatomy · Neurochemistry · Neuroendocrinology · Neuroscience · Psychoneuroimmunology · Physiological Psychology · Psychopharmacology (Index, Outline)
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 potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, an analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.
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 tetrahydro derivative of progesterone 3α-hydroxy-5α-pregnane-20-one (3α,5α-THPROG).
These compounds can act as allosteric modulators of neurotransmitter receptors, such as GABAA, 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 GABAA receptors.
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. Neurosteroids, including ganaxolone have a broad spectrum of activity in animal models. They may have advantages over other GABAA receptor modulators, notably benzodiazepines, in that tolerance does not appear to occur with extended use. 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. The drug continued to demonstrate efficacy in an 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.
Role in antidepressant actionEdit
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. 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 neurosteroidsEdit
Benzodiazepines may influence neurosteroid metabolism by virtue of their actions on translocator protein (TSPO; "peripheral benzodiazepine receptor"). The pharmacological actions of benzodiazepines at the GABAA 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.
- Dehydroepiandrosterone sulfate
- 17-Phenylandrostenol - blocks the effects of neuroactive steroids without affecting responses produced by benzodiazepines or barbiturates
- ↑ Paul SM, Purdy RH (1992). Neuroactive steroids. FASEB J. 6 (6): 2311–22.
- ↑ Lan NC, Gee KW (1994). Neuroactive steroid actions at the GABA-A receptor. Horm Behav 28 (4): 537–44.
- ↑ Reddy DS, Rogawski MA (April 2009). Neurosteroid replacement therapy for catamenial epilepsy. Neurotherapeutics 6 (2): 392–401.
- ↑ Morrow AL (2007). Recent Developments in the Significance and Therapeutic Relevance of Neuroactive Steroids – Introduction to the Special Issue. Pharmacol. Ther. 116 (1): 1–6.
- ↑ Dubrovsky BO (2005). Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (2): 169–92.
- ↑ 6.0 6.1 Farfel G, Tsai J, Shaw K, Nohria V, Rogawski MA (2013). "Ganaxolone" in Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS: Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res. 103: 2–30.
- ↑ Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (2006). Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc. Natl. Acad. Sci. U.S.A. 103 (39): 14602–7.
- ↑ Mellon SH, Griffin LD (2002). Neurosteroids: biochemistry and clinical significance. Trends Endocrinol. Metab. 13 (1): 35–43.
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- ↑ Wu FS, Gibbs TT, Farb DH (1991). Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor. Mol. Pharmacol. 40 (3): 333–6.
- ↑ Maurice T, Junien JL, Privat A (1997). Dehydroepiandrosterone sulfate attenuates dizocilpine-induced learning impairment in mice via sigma 1-receptors. Behav. Brain Res. 83 (1–2): 159–64.
- ↑ Baulieu EE (1997). Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog. Horm. Res. 52: 1–32.
- ↑ Rupprecht R, Reul JM, Trapp T, van Steensel B, Wetzel C, Damm K, Zieglgänsberger W, Holsboer F (1993). Progesterone receptor-mediated effects of neuroactive steroids. Neuron 11 (3): 523–30.
- ↑ Jung-Testas I, Do Thi A, Koenig H, Désarnaud F, Shazand K, Schumacher M, Baulieu EE (1999). Progesterone as a neurosteroid: synthesis and actions in rat glial cells. J. Steroid Biochem. Mol. Biol. 69 (1–6): 97–107.
- ↑ Belelli D, Lambert JJ (2005). Neurosteroids: endogenous regulators of the GABAA receptor. Nat. Rev. Neurosci. 6 (7): 565–75.
- ↑ Rogawski MA, Reddy DS, 2004. Neurosteroids: endogenous modulators of seizure susceptibility. In: Rho, J.M., Sankar, R., Cavazos, J. (Eds.), Epilepsy: Scientific Foundations of Clinical Practice. Marcel Dekker, New York, 2004;319-355.
- ↑ Kokate TG, Yamaguchi S, Pannell LK, et al. (November 1998). Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice. J. Pharmacol. Exp. Ther. 287 (2): 553–8.
- ↑ Reddy DS, Rogawski MA (December 2000). Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself. J. Pharmacol. Exp. Ther. 295 (3): 1241–8.
- ↑ Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A (1998). Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc. Natl. Acad. Sci. U.S.A. 95 (6): 3239–44.
- ↑ Pinna G, Costa E, Guidotti A (2006). Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmacology (Berl.) 186 (3): 362–72.
- ↑ Dhir A, Rogawski MA (October 2011). Role of neurosteroids in the anticonvulsant activity of midazolam. Br J Pharmacol.
- ↑ Usami N, Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A (April 2002). Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines. Biol Pharm Bull 25 (4): 441–5.
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