Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3β-hydroxy-5α-pregnan-20-one (isoallopregnanolone)

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

“…The antagonizing effect of isoallopregnanolone on allopregnanolone seems specific as GABA, benzodiazepine or barbiturate effects are not inhibited by isoallopregnanolone (Lundgren et al 2003;Stromberg et al 2006).…”

“…The only structural difference from its isomer allopregnanolone is the hydroxyl group in 3β-instead of 3α-position. Isoallopregnanolone by its own is, as far as we know today, without hormonal or GABA A receptor effects (Lundgren et al 2003;Stromberg et al 2006). Instead, isoallopregnanolone has often been used as a control when testing the specificity of allopregnanolone and its GABA A receptor enhancing effect, to show that the sterical configuration with the 3-hydroxy group is of major importance for the GABA A receptor stimulating effects of allopregnanolone (Gee et al 1987).…”

“…Furthermore, no isoallopregnanolone influence has been noted on anesthesia (Gyermek et al 1968), anxiolysis (Bitran et al 1991;Wieland et al 1991;Carboni et al 1996;Rodgers and Johnson 1998), antiepileptic effect (Kokate et al 1994), hyperphagic effect (Chen et al 1996) or stimulation of gastric acid secretion (Watanabe et al 2000). Also, in in vitro experiments no effect of isoallopregnanolone of its own has been detected (Peters et al1988;Lan et al 1991;Lambert et al 1995;Dayanithi and Tapia-Arancibia 1996;Le Foll et al 1997;Calogero et al 1998;Concas et al 1998;Lundgren et al 2003).…”

“…However, it has recently been shown that isoallopregnanolone can antagonize the effect of allopregnanolone on the GABA A receptor as shown in vitro (Wang et al 2002, Lundgren et al 2003, on slices of brain tissue (Wang et al 2000) and in vivo as it inhibits allopregnanolone-mediated induction of anesthesia in rats . The antagonizing effect of isoallopregnanolone on allopregnanolone seems specific as GABA, benzodiazepine or barbiturate effects are not inhibited by isoallopregnanolone (Lundgren et al 2003;Stromberg et al 2006).…”

Physiological Relevance of Pregnanolone Isomers and Their Polar Conjugates with Respect to the Gender, Menstrual Cycle and Pregnancy

“…The site of expression of HSD17B2 was identified in endothelial cells of fetal capillaries and some stem villous vessels (Moghrabi, et al, 1997;Takeyama, et al, 1998) and in endothelial cells of villous arteries and arterioles (Bonenfant, Blomquist, et al, 2000) in the close proximity of the fetal circulation. The reversible oxido-reductive interconversion of GABAergic C21 and C19 3Ǐ-hydroxy-5Ǐ/ǐ-reduced metabolites to the corresponding inactive 3-oxo-metabolites and antagonistic 3ǐ-hydroxy-metabolites (catalyzed by HSD17Bs an AKR1C1s) may also influence the balance between neuroinhibitory and neuroexcitatory steroids (Lundgren, et al, 2003). While the reductive conversion in the C3 position produce GABAergic steroids, the conversion of 20-oxo-to 20Ǐ-hydroxy-group or a modification of the C17,20 side chain in the 3Ǐ-hydroxy-5Ǐ/ǐ C21 steroids result in subtype dependent reduction of positive allosteric modulation of GABA A -r (Belelli, Lambert, Peters, Gee, & Lan, 1996).…”