Progesterone and neuroprotection Singh, Meharvan; Su, Chang
Hormones and behavior,
02/2013, Letnik:
63, Številka:
2
Journal Article
Recenzirano
Odprti dostop
This article is part of a Special Issue "Hormones & Neurotrauma".
Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as the experimental ...model. And while estrogen intervention in these animals has, at least partially, restored cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for diseases such as Alzheimer's disease during the postmenopausal period could also be contributed by this loss of progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal models and in humans. Here, we review the evidence that supports the neuroprotective effects of progesterone and discuss the various mechanisms that are thought to mediate these protective effects. We also discuss the receptor pharmacology of progesterone's neuroprotective effects and present a conceptual model of progesterone action that supports the complementary effects of membrane-associated and classical intracellular progesterone receptors. In addition, we discuss fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin, medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined estrogen/progestin arm of the Women's Health Initiative-Memory Study (WHIMS) and suggest that the type of progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain function.
► Reviews the current state of knowledge on progesterone-induced neuroprotection. ► Reviews the receptor pharmacology associated with progesterone-induced protection. ► Reviews the signaling mechanisms that mediate progesterone-induced protection. ► Defines key differences in the neurobiology of progesterone and MPA.
•Cytoplasmic and nuclear progesterone receptor(PR) and PRB expression in human tissues.•PR and PRB distribution in specific types of cells in individual organs.•The comparison between PR and PRB ...H-score with genders and age groups.
Progesterone receptor (PR) is expressed in a wide variety of human tissues, including both reproductive and non-reproductive tissues. Upon binding to the PR, progesterone can display several non-reproductive functions, including neurosteroid activity in the central nervous system, inhibition of smooth muscle contractile activity in the gastrointestinal tract, and regulating the development and maturation of the lung. PR exists as two major isoforms, PRA and PRB. Differential expression of these PR isoforms reportedly contributes to different biological activities of the hormone. However, the distribution of the PR isoforms in human tissues has remained virtually unexplored.
In this study, we immunolocalized PR expression in various human tissues using PR (1294) specific antibody, which is capable of detecting both PRA and PRB, and PRB (250H11) specific antibody. Tissues from the uterus, ovary, breast, placenta, prostate, testis, cerebrum, cerebellum, pituitary, spinal cord, esophagus, stomach, small intestine, colon, pancreas, liver, kidney, urinary bladder, lung, heart, aorta, thymus, adrenal gland, thyroid, spleen, skin, and bone were examined in four different age groups (fetal, pediatric, young, and old) in male and female subjects. PR and PRB were detected in the nuclei of cells in the female reproductive system, in both the nuclei and cytoplasm of pituitary gland and pancreatic acinar cells, and only in the cytoplasm of cells in the testis, stomach, small intestine, colon, liver, kidney, urinary bladder, lung, adrenal gland, and skin. Of particular interest, total PRB expression overlapped with that of total PR expression in most tissues but was negative in the female fetal reproductive system. The findings indicate that progesterone could affect diverse human organs differently than from reproductive organs. These findings provide new insights into the novel biological roles of progesterone in non-reproductive organs.
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•The study of the functions of mPRs requires the ligands that selectively interact only with mPRs.•For the first time, the available information on the structures of compounds ...interacting with mPRs was summarized and analyzed.•Main trends of steroid scaffold modification to develop new selective mPRs ligands are proposed.•Two new mPRs ligands with unique selectivity were found.
Progesterone modulates many processes in the body, acting through nuclear receptors (nPR) in various organs and tissues. However, a number of effects are mediated by membrane progesterone receptors (mPRs), which are members of the progestin and adipoQ (PAQR) receptor family. These receptors are found in most tissues and immune cells. They are expressed in various cancer cells and appear to play an important role in the development of tumors. The role of mPRs in the development of insulin resistance and metabolic syndrome has also attracted attention. Since progesterone efficiently binds to both nPRs and mPRs, investigation of the functions of the mPRs both at the level of the whole body and at the cell level requires ligands that selectively interact with mPRs, but not with nPRs, with an affinity comparable with that of the natural hormone. The development of such ligands faces difficulties primarily due to the lack of data on the three-dimensional structure of the ligand-binding site of mPR. This review is the first attempt to summarize available data on the structures of compounds interacting with mPRs and analyze them in terms of the differences in binding to membrane and nuclear receptors. Based on the identified main structural fragments of molecules, which affect the efficiency of binding to mPRs and are responsible for the selectivity of interactions, we propose directions of modification of the steroid scaffold to create new selective mPRs ligands.
A year-long prospective study characterized the seasonality of oestrus cycles in primiparous, nonpregnant Swakara (n=8) and Damara (n=5) ewes through surveillance of plasma progesterone (P4) levels. ...During this period, Swakara and Damara groups evidently averaged 23 oestrus cycles with an average length of 17 days. Damara ewes showed greater mean peak plasma P4 levels (11.4±0.16ng/ml) than Swakara ewes (5.4±0.11ng/ml) (P<0.05). Oestrus cycles in Damara ewes showed relatively uniform plasma P4 peaks throughout the year ranging from 10.6±0.16 to 12.6±0.24ng/ml. In Swakara ewes, P4 peaks were highest in the autumn oestrus cycles (from 7.1±0.16 to 7.5±0.11ng/ml), rapidly declining through winter to 2.2±0.08ng/ml by midspring and then rapidly increasing to 4.9±0.37ng/ml at the commencement of summer, followed by a gradual increase from 5.7± to 7.1±ng/ml by the start of autumn. The annual mean area under the curve temporal progesterone measurements (AUCPM) in Damara ewes (115.9±18.6ng⁎day/ml) was greater than that in Swakara ewes (58.6±25.3ng⁎day/ml) (p<0.05). For Swakara ewes, the mean AUCPM in summer and autumn cycles (68.2±14.7 and 79.5±10.0ng⁎day/ml, respectively) were greater than those in spring and winter cycles (28.7±12.3 and 55.0±27.3ng⁎day/ml), respectively (P<0.05). There was no seasonal variation in the exposure of the Damara ewes to P4 in between seasons (P>0.05), though, however, the Damara ewes had greater P4 levels than the Swakara ewes (P<0.05). Progesterone profiles showed that Swakara ewes possessed ‘residual’ seasonality, whereas the Damara ewes were no longer seasonal. The implications of this disparity in the seasonal exposure of Swakara and Damara ewes to luteal P4 on fertility warrant further investigation.
Introduction
The aim of this article is to review the physiology of progesterone and focus on its physiological actions on tissues such as endometrium, uterus, mammary gland, cardiovascular system, ...central nervous system and bones. In the last decades, the interest of researchers has focused on the role of progesterone in genomic and non‐genomic receptor mechanisms.
Materials and Methods
We searched PubMed up to December 2014 for publications on progesterone/steroidogenesis.
Results and Conclusions
A better understanding of the biological genomic and non‐genomic receptor mechanisms could enable us in the near future to obtain a more comprehensive knowledge of the safety and efficacy of this agent during hormone replacement therapy (natural progesterone), in vitro fertilization (water‐soluble subcutaneous progesterone), in traumatic brain injury, Alzheimer's disease and diabetic neuropathy, even though further clinical studies are needed to prove its usefulness.
•Multiple receptors contribute to the progesterone effects.•Progesterone and allopregnanolone are neuroprotective.•Local biosynthesis of neurosteroids increased after injury.•Progesterone receptors ...play a key role in neuroprotection.•Neuroprotection by allopregnanolone involves the modulation of GABAA receptors.
Progesterone is a well-known steroid hormone, synthesized by ovaries and placenta in females, and by adrenal glands in both males and females. Several tissues are targets of progesterone and the nervous system is a major one. Progesterone is also locally synthesized by the nervous system and qualifies, therefore, as a neurosteroid. In addition, the nervous system has the capacity to bio-convert progesterone into its active metabolite allopregnanolone. The enzymes required for progesterone and allopregnanolone synthesis are widely distributed in brain and spinal cord. Increased local biosynthesis of pregnenolone, progesterone and 5α-dihydroprogesterone may be a part of an endogenous neuroprotective mechanism in response to nervous system injuries. Progesterone and allopregnanolone neuroprotective effects have been widely recognized. Multiple receptors or associated proteins may contribute to the progesterone effects: classical nuclear receptors (PR), membrane progesterone receptor component 1 (PGRMC1), membrane progesterone receptors (mPR), and γ-aminobutyric acid type A (GABAA) receptors after conversion to allopregnanolone. In this review, we will succinctly describe progesterone and allopregnanolone biosynthetic pathways and enzyme distribution in brain and spinal cord. Then, we will summarize our work on progesterone receptor distribution and cellular expression in brain and spinal cord; neurosteroid stimulation after nervous system injuries (spinal cord injury, traumatic brain injury, and stroke); and on progesterone and allopregnanolone neuroprotective effects in different experimental models including stroke and spinal cord injury. We will discuss in detail the neuroprotective effects of progesterone on the nervous system via PR, and of allopregnanolone via its modulation of GABAA receptors.
Progesterone exerts multiple effects in different tissues through nuclear receptors (nPRs) and through membrane receptors (mPRs) of adiponectin and progestin receptor families. The effect of ...progesterone on the cells through different types of receptors can vary significantly. At the same time, it affects the processes of proliferation and apoptosis in normal and tumor tissues in a dual way, stimulating proliferation and carcinogenesis in some tissues, suppressing them and stimulating cell death in others. In this study, we have shown the presence of high level of mPRβ mRNA and protein in the HepG2 cells of human hepatocellular carcinoma. Expression of other membrane and classical nuclear receptors was not detected. It could imply that mPRβ has an important function in the HepG2 cells. The main goal of the work was to study functions of this protein and mechanisms of its action in human hepatocellular carcinoma cells. Previously, we have identified selective mPRs ligands, compounds LS-01 and LS-02, which do not interact with nuclear receptors. Their employment allows differentiating the effects of progestins mediated by different types of receptors. Effects of progesterone, LS-01, and LS-02 on proliferation and death of HepG2 cells were studied in this work, as well as activating phosphorylation of two kinases, p38 MAPK and JNK, under the action of three steroids. It was shown that all three progestins after 72 h of incubation with the cells suppressed their viability and stimulated appearance of phosphatidylserine on the outer surface of the membranes, which was detected by binding of annexin V, but they did not affect DNA fragmentation of the cell nuclei. Progesterone significantly reduced expression of the proliferation marker genes and stimulated expression of the p21 protein gene, but had a suppressive effect on the expression of some proapoptotic factor genes. All three steroids activated JNK in these cells, but had no effect on the p38 MAPK activity. The effects of progesterone and selective mPRs ligands in HepG2 cells were the same in terms of suppression of proliferation and stimulation of apoptotic changes in outer membranes, therefore, they were mediated through interaction with mPRβ. JNK is a member of the signaling cascade activated in these cells by the studied steroids.
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