Neurosteroids: endogenous role in the human brain and therapeutic potentials - PubMed (original) (raw)

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Neurosteroids: endogenous role in the human brain and therapeutic potentials

Doodipala Samba Reddy. Prog Brain Res. 2010.

Abstract

This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and their therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids, such as allopregnanolone and allotetrahydrodeoxycorticosterone, androstane neurosteroids, such as androstanediol and etiocholanolone, and sulfated neurosteroids such as pregnenolone sulfate. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful anti-seizure activity in diverse animal models. Neurosteroids increase both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety, and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-A receptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy, and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.

Copyright © 2010 Elsevier B.V. All rights reserved.

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Figures

Figure 1

Figure 1. Biosynthetic pathways of neurosteroids in the human brain and their impact on brain function

5α-Reductase converts progesterone, testosterone and deoxycorticosterone into 5α-dihydro reduced steroids, which are then reduced further to 3α-hydroxylated neurosteroids by 3α-HSOR. Testosterone is converted into 17β-estradiol by the aromatase enzyme. These and related enzymes involved in neurosteroid biosynthesis and metabolism are present in the human brain.

Figure 2

Figure 2. Biosynthesis of progesterone- and testosterone-derived neurosteroids in the brain

Androstanediol (5α-androstan-3α,17β-diol) is synthesized from testosterone by reduction at the 5-and 3-positions of the steroid A-ring. Allopregnanolone (5α-pregnan-3α-ol-20-one) is derived from progesterone by reduction at the 5- and 3-positions of the steroid A-ring. Androstanediol differs from allopregnanolone by a 17β-hydroxyl group instead of 17β-methyl-carbonyl group.

Figure 3

Figure 3. Neurosteroid potentiation of GABA-A receptor-mediated currents

(A) Neurosteroids have specific allosteric binding site on the GABA-A receptors, which are pentameric structures made of 2α, 2β,1γ or δ subunit that form chloride ion channel. The binding site(s) for the neurosteroids is separate from that of the benzodiazepine and barbiturate sites. (B) The neurosteroid androstanediol causes an increase in GABA-gated chloride currents in acutely dissociated hippocampal CA1 neurons in the whole-cell patch-clamp electrophysiological recordings. (C) The concentration-dependent increase in GABA potentiation by androstanediol in CA1 neurons.

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