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Neuroactive steroid

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Apart from exerting effects on the genome via intracellular steroid receptors, neuroactive steroids (or neurosteroids) 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.

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 3 beta-hydroxy-delta 5-compounds, such as pregnenolone (PREG) and dehydroepiandrosterone (DHEA), their sulfates, and reduced metabolites such as the tetrahydroderivative of progesterone 3 alpha-hydroxy-5 alpha-pregnane-20-one (3 alpha,5 alpha-THPROG). These compounds can act as allosteric modulators of neurotransmitter receptors, such as GABA(A), NMDA, and sigma receptors. Progesterone (PROG) is also a neurosteroid, and a progesterone receptor (PROG-R) has been identified in peripheral and central glial cells.

[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [10] [11] [12] [13] [14] [15] [16]

References[edit | edit source]

  1. ↑ Herd MB, Belelli D, Lambert JJ (2007). "Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors". doi:10.1016/j.pharmthera.2007.03.007. PMID 17531325.
  2. ↑ Hosie AM, Wilkins ME, da Silva HM, Smart TG (2006). "Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites". Nature. 444 (7118): 486–9. doi:10.1038/nature05324. PMID 17108970.
  3. ↑ 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. doi:10.1073/pnas.0606544103. PMID 16984997.
  4. ↑ Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S (2005). "Neurosteroid access to the GABAA receptor". J. Neurosci. 25 (50): 11605–13. doi:10.1523/JNEUROSCI.4173-05.2005. PMID 16354918.
  5. ↑ Belelli D, Lambert JJ (2005). "Neurosteroids: endogenous regulators of the GABAA receptor". Nat. Rev. Neurosci. 6 (7): 565–75. doi:10.1038/nrn1703. PMID 15959466.
  6. ↑ 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. doi:10.1007/s00213-005-0213-2. PMID 16432684.
  7. ↑ 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.
  8. ↑ Dubrovsky BO (2005). "Steroids, neuroactive steroids and neurosteroids in psychopathology". Prog. Neuropsychopharmacol. Biol. Psychiatry. 29 (2): 169–92. doi:10.1016/j.pnpbp.2004.11.001. PMID 15694225.
  9. ↑ Mellon SH, Griffin LD (2002). "Neurosteroids: biochemistry and clinical significance". Trends Endocrinol. Metab. 13 (1): 35–43. doi:10.1016/S1043-2760(01)00503-3. PMID 11750861.
  10. ↑ 10.0 10.1 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. doi:10.1073/pnas.051628598. PMID 11226329.
  11. ↑ 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. doi:10.1073/pnas.95.6.3239. PMID 9501247.
  12. ↑ 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.
  13. ↑ 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. PMID 8398145.
  14. ↑ Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E (1990). "Neurosteroids act on recombinant human GABAA receptors". Neuron. 4 (5): 759–65. PMID 2160838.
  15. ↑ Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986). "Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor". Science. 232 (4753): 1004–7. doi:10.1126/science.2422758. PMID 2422758.
  16. ↑ 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. PMID 6458035.

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