Anticonvulsant Activity of Progesterone and Neurosteroids in Progesterone Receptor Knockout Mice

Abstract

Many of the biological actions of progesterone are mediated through the progesterone receptor (PR), a nuclear transcription factor. Progesterone is well recognized to protect against seizures in animal models. Although this activity has been attributed to the progesterone metabolite allopregnanolone, a GABA A receptor-modulating neurosteroid with anticonvulsant properties, PRs could also play a role. Here, we used PR knockout (PRKO Ϫ/Ϫ ) mice bearing a targeted deletion of the PR gene that eliminates both isoforms of the PR to investigate the contribution of the PR to the anticonvulsant activity of progesterone. The protective activity of progesterone was examined in female and male homozygous PRKO mice and isogenic wild-type controls in the pentylenetetrazol (PTZ), maximal electroshock, and amygdala-kindling seizure models. In all three models, the anticonvulsant potency of progesterone was undiminished in PRKO mice compared with control mice. On the contrary, there was a substantial increase in the anticonvulsant potency of progesterone in the PTZ and kindling models. The antiseizure activity of progesterone in PRKO mice was reversed by pretreatment with finasteride, a 5␣-reductase inhibitor that blocks the metabolism of progesterone to allopregnanolone. Unlike progesterone, the neurosteroids allopregnanolone and allotetrahydrodeoxycorticosterone exhibited comparable anticonvulsant potency in PRKO and wild-type mice. The basis for the heightened progesterone responsiveness of PRKO mice is not attributable to pharmacokinetic factors, because the plasma allopregnanolone levels achieved after progesterone administration were not greater in the PRKO mice. These studies provide strong evidence that the PR is not required for the antiseizure effects of progesterone, which mainly occurs through its conversion to the neurosteroid allopregnanolone.

Regional Differences in the Decay Kinetics of GABAAReceptor-Mediated Miniature IPSCs in the Dorsal Horn of the Rat Spinal Cord Are Determined by Mitochondrial Transport of Cholesterol

“…Moreover, a single subcutaneous injection of progesterone mimicked the effect of incubating the spinal cord slices with precursors of AP, suggesting that peripheral fluctuations in steroid or steroid precursor levels might affect the production of neurosteroids in the spinal cord. Similar observations have been made in other areas of the CNS after peripheral injections of steroids (Reddy et al, 2004(Reddy et al, , 2005 or after endogenous fluctuations of steroid levels associated with ovarian cycle (Maguire and Mody, 2007) or stress (Reddy and Rogawski, 2002).…”

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

“…3α-Androstanediol is structurally similar to allopregnanolone and conferred seizure protection in the 6-Hz electroshock model of epilepsy (Kaminski et al, 2004). Overall, the anticonvulsant profile of 3α-androstanediol is highly consistent with other GABA A receptor modulating neurosteroids including allopregnanolone and THDOC, which have similar spectrum of anticonvulsant activity in animal seizure models (Belelli et al, 1989;Kokate et al, 1994;Reddy and Rogawski, 2002;Reddy et al, 2004;Reddy, 2006).…”

“…It is suggested that the sex differences could be due to steroid hormones or sexually dimorphic characteristics in specific brain areas relevant to epilepsy (Cooke et al, 1999;Reddy, 2003b;Ravizza et al, 2003). Current experimental evidence indicates that progesterone-and testosterone-derived neurosteroids could be involved in sexual dimorphism in neural excitability and seizure susceptibility (Cooke et al, 1999;Reddy et al, 2004;Reddy, 2006). The progesterone-derived neurosteroid allopregnanolone is a powerful GABA A receptor-modulating neurosteroid with anticonvulsant properties (Reddy et al, 2001;.…”

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

“…Endogenous neurosteroids are potent allosteric agonists of GABA-A receptors. Allopregnanolone (3-hydroxy-5-pregnan-20-one, AP) is an endogenous neurosteroid with potent antiseizure effects mediated by GABA-A receptors (Reddy et al, 2014;Clossen and Reddy, 2017a). Neurosteroids have a greater sensitivity for GABA-A receptors, which are highly expressed in the dentate gyrus (Brown et al, 2002;Bianchi and Macdonald, 2003;Carver and Reddy, 2013;.…”