3β-Methyl-Neurosteroid Analogs Are Preferential Positive Allosteric Modulators and Direct Activators of Extrasynapticδ-Subunitγ-Aminobutyric Acid Type A Receptors in the Hippocampus Dentate Gyrus Subfield

Abstract

Abstract, 253 words Introduction, 622 words

Serum levels of allopregnanolone, progesterone and testosterone in menstrually-related and postmenopausal migraine: A cross-sectional study

“…Among these, allopregnanolone (3α,5α-tetrahydroprogesterone), a derivative of pregnenolone and progesterone, shows neuroprotective, sedative, anesthetic, anxiolytic and antiepileptic properties. These effects depend mostly on allopregnanolone’s ability to act as a positive allosteric modulator of the GABA(A) receptor complex and therefore on its inhibitory effect on neuronal excitability ( 4 , 5 ). In addition, allopregnanolone has proved to exert analgesic effects and the capability to prevent or reverse maladaptive changes and painful behaviours that occur after nervous system damage in various experimental neuropathic conditions, including chemotherapy-evoked neuropathic pain in rats ( 6 ).…”

Extrasynaptic γ‐aminobutyric acid type A receptor–mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures

“…In males, the neurosteroid 3α‐androstanediol (5α‐androstane‐3α,17β‐diol [AD]) is synthesized from testosterone within the brain. Similar to the mechanism of action of AP, AD allosterically binds γ‐aminobutyric acid type A (GABA‐A) receptors, potentiating channel current, and thereby inhibiting neuronal excitability and seizures …”

“…[12][13][14] In males, the neurosteroid 3α-androstanediol (5α-androstane-3α,17β-diol [AD]) is synthesized from testosterone within the brain. Similar to the mechanism of action of AP, 15,16 AD allosterically binds γ-aminobutyric acid type A (GABA-A) receptors, potentiating channel current, and thereby inhibiting neuronal excitability and seizures. 16,17 Neurosteroids act on both synaptic (γ 2 -containing) and extrasynaptic (δ-containing) GABA-A receptors to regulate neuronal excitability.…”

Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells

“…Methylation at the 3β position of ganaxolone impairs its metabolism to inactive metabolites, thereby increasing its period of effectiveness in inhibiting seizures compared to allopregnanolone ( 26 ). Like allopregnanolone, ganaxolone is an allosteric modulator of GABA- A receptors and acts through different allosteric binding sites to that of benzodiazepines, as revealed by ligand binding assays and receptor mutational analysis ( 17 , 27 , 28 ).…”