Abstract
The neurosteroids progesterone and allopregnanolone regulate numerous neuroprotective functions in neural tissues including inhibition of epileptic seizures and cell death. Many of progesterone's actions are mediated through the nuclear progesterone receptor (PR), while allopregnanolone is widely considered to be devoid of hormonal activity and instead acts through modulation of GABA-A receptor activity. However, allopregnanolone can also exert hormonal actions in neuronal cells through binding and activating membrane progesterone receptors (mPRs) belonging to the progestin and adipoQ receptor (PAQR) family. The distribution and functions of the five mPR subtypes (α, β, γ, δ, ε) in neural tissues are briefly reviewed. mPRδ has the highest binding affinity for allopregnanolone and is highly expressed throughout the human brain. Low concentrations (20 nM) of allopregnanolone act through mPRδ to stimulate G protein (Gs)-dependent signaling pathways resulting in reduced cell death and apoptosis in mPRδ-transfected cells. The 3-methylated synthetic analog of allopregnanolone, ganaxolone, is currently undergoing clinical trials as a promising GABA-A receptor-selective antiepileptic drug (AED). New data show that low concentrations (20 nM) of ganaxolone also activate mPRδ signaling and exert anti-apoptotic actions through this receptor. Preliminary evidence suggests that ganaxolone can also exert neuroprotective effects by activating inhibitory G protein (Gi)-dependent signaling through mPRα and/or mPRβ in neuronal cells. The results indicate that mPRs are likely intermediaries in multiple actions of natural and synthetic neurosteroids in the brain. Potential off-target effects of ganaxolone through activation of mPRs in patients receiving long-term treatment for epilepsy and other disorders should be considered and warrant further investigation.
Highlights
Progesterone and its metabolites produced in neural tissues such as allopregnanolone mediate a wide variety of actions in the brain including neuroprotection, anti-apoptosis, inhibition of epileptic seizures, reproductive behaviors, neuroendocrine control of reproduction, and both pro-tumorigenesis and anti-tumorigenesis [1,2,3]
Evidence has accumulated that some of these actions may be mediated through membrane progesterone receptors [4, 10, 11], 7-transmembrane receptors coupled to G proteins belonging to the progestin and adipoQ receptor (PAQR) family which is unrelated to the GPCR superfamily [12, 13]
Our results suggest that allopregnanolone and the synthetic neurosteroid, ganaxolone, can exert protective functions in cultured neuronal cells through activation of membrane progesterone receptors (mPRs) to attenuate cell death and apoptosis
Summary
Progesterone and its metabolites produced in neural tissues (neurosteroids, Figure 1A) such as allopregnanolone mediate a wide variety of actions in the brain including neuroprotection, anti-apoptosis, inhibition of epileptic seizures, reproductive behaviors, neuroendocrine control of reproduction, and both pro-tumorigenesis and anti-tumorigenesis [1,2,3]. Recent studies with cultured neuronal cells show that low concentrations of progesterone and allopregnanolone exert hormonal actions through binding and activating mPRs, resulting in rapid induction of intracellular signaling pathways and anti-apoptosis [14, 15]. Treatments with 20 nM ganaxolone and allopregnanolone mimicked the effects of progesterone and the mPR-selective agonist, 02-0, to decrease cAMP production in H19-7 cells (Figure 2D), indicating an inhibitory G protein is activated. These results suggest these neurosteroids act through mPRα and/or mPRβ in H19-7 cells, rather than through mPRδ, since mPRα and mPRβ activate inhibitory G proteins
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