Neurosteroids

Neurosteroids

1. Definition & conceptual framework

• Neurosteroids (neuroactive steroids) are steroid molecules that rapidly alter neuronal excitability through non-genomic membrane actions — chiefly allosteric modulation of ligand-gated ion channels — rather than the slow genomic action of classical steroid hormones (FDA mechanism class statement, ZULRESSO/ZURZUVAE/ZTALMY labels: "neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator").
  • Terminology distinction used in the field: "neurosteroid" (Baulieu's original term) = steroid synthesised de novo within the nervous system; "neuroactive steroid" = any steroid (CNS-derived, peripherally-derived, or synthetic) that is pharmacologically active on neuronal targets. The two terms are used interchangeably in regulatory labelling.
• The therapeutically exploited core action is positive allosteric modulation (PAM) of the GABA_A receptor, the principal inhibitory ionotropic receptor of the CNS — the same receptor complex on which benzodiazepines and barbiturates act, but at a pharmacologically distinct steroid-recognition site (G&G 14e Ch.22, pp.428–9 for the multiple-allosteric-site model; FDA labels for the steroid-PAM classification).
• Clinical relevance: neurosteroid PAMs are the first mechanistically novel GABAergic drug class in decades, validated by three FDA approvals 2019–2023 across mood disorders (brexanolone, zuranolone — postpartum/major depression) and epilepsy (ganaxolone — CDKL5 deficiency disorder).