Neurosteroids and their potential as a safer class of general anesthetics

Abstract

Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and they play important biological roles in brain development, brain function and as mediators of mood. One class of NS, 3α-hydroxy-pregnane steroids such as allopregnanolone (AlloP) or pregnanolone (Preg), inhibits neuronal excitability; these endogenous NS and their analogues have been therapeutically applied as anti-depressants, anti-epileptics and general anesthetics. While NS have many favorable properties as anesthetics (e.g. rapid onset, rapid recovery, minimal cardiorespiratory depression, neuroprotection), they are not currently in clinical use, largely due to problems with formulation. Recent advances in understanding NS mechanisms of action and improved formulations have rekindled interest in development of NS as sedatives and anesthetics. In this review, the synthesis of NS, and their mechanism of action will be reviewed with specific emphasis on their binding sites and actions on γ-aminobutyric acid type A (GABA_A) receptors. The potential advantages of NS analogues as sedative and anesthetic agents will be discussed.

Keywords: Allopregnanolone; Alphaxalone; GABAA receptor; Neurosteroids.

Fig. 1

Chemical structure of cholesterol, allopregnanolone, progesterone and the synthetic anesthetic neurosteroids (alphaxalone and hydroxydione). Cholesterol has 27 carbons with a hydrocarbon (isooctyl) tail, a central steroid nucleus composed of four hydrocarbon rings (A, B, C, and D), and a hydroxyl group. The numbering of the carbon atoms indicates their position on the steroid ring or hydrocarbon tail. C3 is a carbon located on the A ring (circled), and 3-OH indicates that the hydroxyl group is connected to C3. The stereochemical configuration of the groups at the 3, 17, 18, 19, and 21 positions are shown by a dashed wedge (α-configuration) or a solid wedge (β-configuration). Note that cholesterol has a 3β-OH, whereas allopregnanolone and alphaxalone have 3α-OH groups. Progesterone and hydroxydione have ketone groups at C3

Fig. 2

Biosynthetic pathways of neurosteroids. Abbreviations: 3α-HSD: 3α hydroxysteroid dehydrogenase, 3β-HSD: 3β hydroxysteroid dehydrogenase, AlloP: allopregnanolone, DHEA: dehydroepiandrosterone, DHEAS: dehydroepiandrosterone sulfate, DOC: deoxycorticosterone, Epi-AlloP: epi-allopregnanolone, P450scc: P450 side-chain cleavage, Preg: pregnanolone, PS: pregnenolone sulfate, StAR: steroidogenic acute regulatory protein, SULT: sulfotransferase, THDOC: tetrahydrodeoxycorticosterone

Fig. 3

Model structures of GABA_A receptor and neurosteroid binding sites. (a) Cryogenic-EM structure showing the side view and top view of GABA_A receptor α1β3γ2 (PDB: 6I53). (b) α-subunits of GABA_A receptor α1β3γ2 (PDB: 6I53) and pore. (c–e) X-ray crystallographic structures of GABA_A receptor TMD intersubunit site with ligand. (c) GLIC-GABA_A receptor—THDOC (PDB: 5OSB). (d) β3 ECD-α5 TMD GABA_A receptor—Preg (PDB: 5O8F). (e) ELIC-GABA_A receptor—alphaxalone (PDB: 6CDU). (f) GABA_A receptor α1β2γ2—AlloP (PDB: 8SI9)