Journal of Neurobiology
Volume 66, Issue 9 , Pages 916 - 928
Published Online: 6 Jun 2006
Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective
Iratxe Ciriza 1, Paloma Carrero 1, Cheryl A. Frye 2, Luis M. Garcia-Segura 1*
1Instituto Cajal, C.S.I.C., Avenida Doctor Arce 37, E-28002 Madrid, Spain
2Department of Psychology, Department of Biology and The Center for Neuroscience Research, The University at Albany-SUNY, 1400 Washington Avenue, Albany, New York 12222
email: Luis M. Garcia-Segura ( lmgs@cajal.csic.es )
*Correspondence to Luis M. Garcia-Segura, Instituto Cajal, C.S.I.C., Avenida Doctor Arce 37, E-28002 Madrid, Spain
Funded by:
Ministerio de Educacion y Ciencia, Spain; Grant Number: SAF 2005-00272
National Science Foundation; Grant Number: IBN03-16083
Keywords
dihydroprogesterone o finasteride o indomethacin o kainic acid o tetrahydroprogesterone
Abstract
The ovarian hormone progesterone is neuroprotective in different experimental models of neurodegeneration. In the nervous system, progesterone is metabolized to 5 -dihydroprogesterone (DHP) by the enzyme 5 -reductase. DHP is subsequently reduced to 3 ,5 -tetrahydroprogesterone (THP) by a reversible reaction catalyzed by the enzyme 3 -hydroxysteroid dehydrogenase. In this study we have analyzed whether progesterone metabolism is involved in the neuroprotective effect of the hormone in the hilus of the hippocampus of ovariectomized rats injected with kainic acid, an experimental model of excitotoxic cell death. Progesterone increased the levels of DHP and THP in plasma and hippocampus and prevented kainic-acid-induced neuronal loss. In contrast to progesterone, the synthetic progestin medroxyprogesterone acetate (MPA, Provera) did not increase DHP and THP levels and did not prevent kainic-acid-induced neuronal loss. The administration of the 5 -reductase inhibitor finasteride prevented the increase in the levels of DHP and THP in plasma and hippocampus as a result of progesterone administration and abolished the neuroprotective effect of progesterone. Both DHP and THP were neuroprotective against kainic acid. However, the administration of indomethacin, a 3 -hydroxysteroid dehydrogenase inhibitor, blocked the neuroprotective effect of both DHP and THP, suggesting that both metabolites are necessary for the neuroprotective effect of progesterone. In conclusion, our findings indicate that progesterone is neuroprotective against kainic acid excitotoxicity in vivo while the synthetic progestin MPA is not and suggest that progesterone metabolism to its reduced derivatives DHP and THP is necessary for the neuroprotective effect of the hormone. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006
Received: 5 January 2006; Accepted: 26 March 2006
10.1002/neu.20293
http://www3.interscience.wiley.com/cgi-bin/abstract/112650754/ABSTRACT
Developmental Neurobiology
Volume 67, Issue 4 , Pages 510 - 520
Published Online: 1 Feb 2007
Copyright © 2007 Wiley Periodicals, Inc
Effects of progesterone and its reduced metabolites, dihydroprogesterone and tetrahydroprogesterone, on the expression and phosphorylation of glycogen synthase kinase-3 and the microtubule-associated protein Tau in the rat cerebellum
Christian Guerra-Araiza 1 2 , Miguel A.R. Amorim 1, Ignacio Camacho-Arroyo 2, Luis M. Garcia-Segura 1*
1Instituto Cajal, CSIC, E-28002 Madrid, Spain
2Departamento de Biologia, Facultad de Quimica, Universidad Nacional Autonoma de Mexico, Mexico, DF, Mexico
email: Luis M. Garcia-Segura ( lmgs@cajal.csic.es )
*Correspondence to Luis M. Garcia-Segura, Instituto Cajal, CSIC, E-28002 Madrid, Spain
Funded by:
Ministerio de Educacion y Ciencia, Spain; Grant Number: SAF 2005-00272
Keywords
gonadal hormones o hypothalamus o microtubules o neuroactive steroids o steroid metabolism
Abstract
Progesterone exerts a variety of actions in the brain, where it is rapidly metabolized to 5 -dihydroprogesterone (DHP) and 3 ,5 -tetrahydroprogesterone (THP). The effect of progesterone and its metabolites on the expression and phosphorylation of the microtubule-associated protein Tau and glycogen synthase kinase 3 (GSK3 ), a kinase involved in Tau phosphorylation, were assessed in two progesterone-sensitive brain areas: the hypothalamus and the cerebellum. Administration of progesterone, DHP, and THP to ovariectomized rats did not affect Tau and GSK3 assessed in whole hypothalamic homogenates. In contrast, progesterone and its metabolites resulted in a significant decrease in the expression of Tau and GSK3 in the cerebellum. Furthermore, progesterone administration resulted in an increase in the phosphorylation of two epitopes of Tau (Tau-1 and PHF-1) phosphorylated by GSK3 , but did not affect the phosphorylation of an epitope of Tau (Ser262) that is GSK3 insensitive. These effects were accompanied by a decrease in the phosphorylation of GSK3 in serine, which is associated to an increase in its activity, suggesting that the effect of progesterone on Tau-1 and PHF-1 phosphorylation in the cerebellum is mediated by GSK3 . The regulation of Tau expression and phosphorylation by progesterone may contribute to the hormonal regulation of cerebellar function by the modification of neuronal cytoskeleton. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007
Received: 30 October 2006; Revised: 4 December 2006; Accepted: 11 December 2006
10.1002/dneu.20383
http://www3.interscience.wiley.com/cgi-bin/abstract/114108849/ABSTRACT
The Future of Hormone Therapy: What Basic Science and Clinical Studies Teach Us
Volume 1052 published June 2005
Ann. N.Y. Acad. Sci. 1052: 145-151 (2005). doi: 10.1196/annals.1347.010
Copyright © 2005 by the New York Academy of Sciences
Mechanisms of Progesterone-Induced Neuroprotection
MEHARVAN SINGH
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
Address for correspondence: Meharvan Singh, Ph.D., Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107. Voice: 817-735-5429; fax: 817-735-0408. msingh@hsc.unt.edu
ABSTRACT
Gonadal steroid hormones such as estrogen and progesterone can no longer be considered strictly within the confines of reproductive function, and with respect to their anatomic targets, extrahypothalamic structures within the brain such as the cerebral cortex have revealed themselves to be important targets. As such, it may come as no surprise that the decline in such hormones, which occurs after the menopause or ovariectomy, can result in neuronal dysfunction. Although estrogen has been shown to help restore the deficits consequent to ovariectomy, it is important to consider that ovariectomy, like the menopause, results in the precipitous loss of not only estrogen but of progesterone as well. As such, the loss of progesterone may contribute to the deficits observed after ovariectomy or the increased risk for Alzheimer's disease seen after the menopause. Indeed, recent evidence supports the neuroprotective potential of progesterone itself. Here, we review the current understanding of some of the diverse mechanisms by which progesterone may reduce neuronal vulnerability to toxic insults relevant to age and age-associated diseases such as Alzheimer's disease. Further, we comment on the need to carefully consider the various preparations of progestins that are currently available and argue that "not all progestins are created equal," at least when it comes to influences on neuroprotection and other extrahypothalamic brain functions.
Progesterone is a major gonadal hormone that is synthesized primarily by the ovary (corpus luteum) in the female and by the testes and adrenal cortex in the male. Although progesterone levels are generally higher in the female, it is worth noting that levels of progesterone during the female follicular phase of the menstrual cycle are similar to those seen in males, suggesting that progesterone plays an equally important role in both males and females. The paradigmatic mechanism by which progesterone elicits its effects is through the progesterone receptor (PR), which like estrogen receptors (ERs), has classically been described as a nuclear transcription factor, acting through specific progesterone response elements (PREs) within the promoter region of target genes to regulate transcription. Such a mechanism may be relevant to the regulation of neurotrophin expression, which also appears to be regulated by progesterone. 1
Two major isoforms of the classical progesterone receptor exist, PR-B, and its N-terminally truncated form, PR-A. The latter has been shown to exert negative control of not only PR-B-mediated transcription but that mediated by the ER and glucocorticoid receptor as well. This negative regulation of ER function by a PR may underlie, at least in part, the mechanism by which progestins functionally antagonize the effects of estrogen. For example, progestins inhibit estrogen's ability to increase serum levels of 1,25-dihydroxy vitamin D, 2 whose consequence may be to antagonize estrogen's beneficial effects on bone. However, the interaction between the two receptors may not only result in transrepression but may also be cooperative in nature. For example, Migliaccio et al. 3 demonstrated a physical interaction of the progesterone receptor with the ER in mammary tumor cells and that this association was necessary for progesterone to elicit the activation of the mitogen-activated protein kinase (MAPK) pathway. Further, the ability of progesterone to stimulate the MAPK pathway was blocked not only by a PR antagonist but also by an ER antagonist. 3
As introduced in the preceding paragraph, progesterone can also elicit its effects via nongenomic mechanisms (such as the activation of typically growth factor-associated signal transduction pathways). The growing list of second-messenger/signal transduction systems activated by progesterone includes cAMP/PKA, 4MAPK (ERK1/2), 3,5 and the PI-3K/Akt pathway. 5 Activation of such signaling pathways may not only be relevant to how progesterone regulates cellular function related to reproduction but may also be an important mechanism by which progesterone elicits its neuroprotective effects. For example, progesterone-induced neuroprotection has not only been correlated with activation of the MAPK and Akt signaling pathways 6,7 but has also been shown to depend on the activation of the MAPK pathway. 1
As mediators of these nongenomic effects, the classical receptor has been implicated, but depending on the cellular context, a novel receptor system for progesterone may also be involved. For example, progesterone may exert its effects via interactions with membrane binding sites, characterized in the brain by the demonstration of specific, displaceable binding in synaptosomal membrane preparations. 8,9 Such membrane binding sites may include the recently cloned membrane progesterone receptor that exhibits characteristics of G protein-coupled receptors. 10,11 Progesterone, through its metabolites, can also interact with membrane-associated receptors coupled to ion channels, such as the GABA A receptor system (see Ref. 12 for review). Such metabolites include allopreganolone (or 3 ,5 -tetrahydroprogesterone), which can bind to discrete sites within the hydrophobic domain of the GABA A receptor complex and result in the potentiation of GABA-induced chloride conductance-and in turn may regulate cellular excitability and thus, excitotoxicity. Thus, progesterone's ability to interact with specific sites within the membrane (either membrane-binding sites [receptors] or with the GABA A receptor), as well as with specific cytosolic signal transducers, may help explain some of the rapid effects of progesterone, which in addition to its classical genomic mechanisms, may be important for regulating cell viability. Alternatively, the parent compound, progesterone, may also have effects on the GABA A receptor, albeit indirect. For example, progesterone may influence the GABA A receptor via the activation of a signal transduction pathway, which in turn, influences GABA-gated currents through phosphorylation of discrete sites within certain subunits of the GABA A receptor. 13,14
PROGESTERONE-INDUCED NEUROPROTECTION
A considerable amount of information has been obtained regarding the mechanisms underlying estrogen's protective effects. One experimental model that has been valuable in the validation of the hypothesis that estrogens are beneficial is the use of the ovariectomized animal. Ovariectomy results in impaired cellular function that is reflected by behavioral, neurochemical, and molecular deficits consistent with those seen with advanced age or in certain age-associated diseases like Alzheimer's disease. Estrogen treatment of ovariectomized animals at least partially normalizes the deficits. 15-17 It is important to recognize, however, that ovariectomy results in the loss of not only the primary forms of circulating estrogen but also of another major ovarian hormone, progesterone. Thus, the behavioral, neurochemical, and molecular deficits that resulted from ovariectomy may not only have been due to a loss in circulating estrogen levels but may also have been a consequence of progesterone loss. Moreover, estrogen replacement does not always lead to the complete recovery of the ovariectomy-induced deficit. 17 As such, this partial normalization could be a result of not having replaced the other steroid hormones similarly lost following ovariectomy.
In humans, the menopause is also characterized by the concomitant loss of progesterone, and not just estrogen. As such, the increased risk for developing Alzheimer's disease may be contributed by the precipitous decline in both estrogen and progesterone levels. Thus, it is possible that progesterone is equally beneficial, either alone or in conjunction with estrogen.
In fact, progesterone, like estrogen, has been reported to have neuroprotective effects in various experimental models. In hippocampal neurons, both estradiol and progesterone were shown to reduce neuronal vulnerability to such insults as glutamate, FeSO4, and Aß toxicity. 18 In addition, secondary neuronal loss following cortical contusion injury and resulting cognitive impairment was significantly reduced in mice that received progesterone treatment relative to that of untreated controls. 19,20 Progesterone was also effective at reducing the amount of cell death seen in an acute model of global ischemia. 21 Further, progesterone was protective against excitotoxic insult and promoted morphological and functional recovery in the Wobbler mouse, an animal model of spinal cord degeneration. 22,23
Mechanistically, progesterone-induced neuroprotection may be mediated by multiple mechanisms. The effects of progesterone on neurotrophin expression may be mediated by the classical mechanism of transcriptional activation. Alternatively, progesterone may act through novel receptor systems (membrane PR or the GABA A receptor) to regulate cellular events that are important for neuroprotection. For example, metabolites of progesterone, such as allopregnanolone, can bind to a site within the GABA A receptor complex, and as a consequence, potentiate the effect of GABA on its receptor (see Ref. 12 for review). This activation of the GABA A receptor, in turn, has been shown to modulate cell survival, particularly in models of excitotoxicity, and may be consistent with the protective effect of progesterone seen against kainate-induced seizure activity and subsequent cell death. 24 Progesterone may also be protective through its ability to elicit the activation of specific signaling pathways relevant to neuroprotection, 5,6 as well as increasing the expression of antiapoptotic proteins such as Bcl-2. 6 Finally, progesterone has been described to have antioxidant effects 25 that may also contribute to neuronal survival following injury. Collectively, these data support the multiple mechanisms by which progesterone is protective and supports the importance of progesterone, either alone or in combination with estrogen, in promoting cell survival.
CLINICAL USES OF PROGESTINS
The major form of progestin used in hormone therapy (HT) is the synthetic compound medroxyprogesterone acetate (MPA), which is the major progestin used in the formulation of hormone therapy and oral contraceptives. With regards to HT, the role of the progestin is to counteract the uterotrophic effects of estrogen or an apparent increase in risk for certain cancers like uterine cancer resulting from unopposed estrogen treatment (for review, see Ref. 26 ). The natural hormone, progesterone (Prometrium®), is also used, though to a lesser degree in the United States. Although both the synthetic progestins and the natural hormone, progesterone, can elicit similar effects (i.e., both can inhibit the uterotrophic effects of estrogen and can exert an inhibitory influence [negative feedback] on gonadotropin secretion at the level of the hypothalamus), it is important to recognize that these hormones do exhibit important differences, particularly in relation to their effects on the brain. For example, progesterone has been described to be neuroprotective, 6,18 whereas the synthetic progestin, MPA, was not. 6 Moreover, MPA antagonized the effects of estrogen, whereas the natural hormone progesterone did not. 6,7,27 Such differences may be important in considering the results of the recently published WHI studies which used MPA rather than progesterone, and further, could provide critical insight into the development of the most effective therapeutic formulations for the treatment of various postmenopausal conditions.
ACKNOWLEDGMENTS
Part of the work cited in this review was supported by NIH Grants AG 22550 and AG 23330 and a Young Investigator Award from NARSAD (National Alliance on Research in Schizophrenia and Depression).
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http://www.annalsnyas.org/cgi/content/full/1052/1/145
Mol Chem Neuropathol. 1997 May;31(1):1-11. Links
Progesterone protects against lipid peroxidation following traumatic brain injury in rats.
Roof RL ,
Hoffman SW ,
Stein DG .
Department of Psychology Texas Christian University, Fort Worth 76129, USA.
The gonadal hormone, progesterone, has been shown to have neuroprotective effects in injured nervous system, including the severity of postinjury cerebral edema. Progesterone's attenuation of edema is accompanied by a sparing of neurons from secondary neuronal death and with improvements in cognitive outcome. In addition, we recently reported that postinjury blood-brain barrier (BBB) leakage, as measured by albumin immunostaining, was significantly lower in progesterone treated than in nontreated rats, supporting a possible protective action of progesterone on the BBB. Because lipid membrane peroxidation is a major contributor to BBB breakdown, we hypothesized that progesterone limits this free radical-induced damage. An antioxidant action, neuroprotective in itself, would also account for progesterone's effects on the BBB, edema, and cell survival after traumatic brain injury. To test progesterone's possible antiperoxidation effect, we compared brain levels of 8-isoprostaglandin F2 alpha (8-isoPGF2 alpha), a marker of lipid peroxidation, 24, 48, and 72 h after cortical contusion in male rats treated with either progesterone or the oil vehicle. The brains of progesterone treated rats contained approximately one-third of the 8-isoPGF2 alpha found in oil-treated rats. These data suggest progesterone has antioxidant effects and support its potential as a treatment for brain injury.
PMID: 9271001 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9271001&dopt=Citation
Science 9 June 1995:
Vol. 268. no. 5216, pp. 1500 - 1503
DOI: 10.1126/science.7770777
Articles
Science, Vol 268, Issue 5216, 1500-1503
Copyright © 1995 by American Association for the Advancement of Science
Progesterone synthesis and myelin formation by Schwann cells
HL Koenig, M Schumacher, B Ferzaz, AN Thi, A Ressouches, R Guennoun, I Jung-Testas, P Robel, Y Akwa, and EE Baulieu
Laboratoire Neurobiologie du Developpement, Universite Bordeaux I, Talence, France.
Progesterone is shown here to be produced from pregnenolone by Schwann cells in peripheral nerves. After cryolesion of the sciatic nerve in male mice, axons regenerate and become myelinated. Blocking either the local synthesis or the receptor-mediated action of progesterone impaired remyelination. Administration of progesterone or its precursor, pregnenolone, to the lesion site increased the extent of myelin sheath formation. Myelination of axons was also increased when progesterone was added to cultures of rat dorsal root ganglia. These observations indicate a role for locally produced progesterone in myelination, demonstrate that progesterone is not simply a sex steroid, and suggest a new therapeutic approach to promote myelin repair.
http://www.sciencemag.org/cgi/content/abstract/268/5216/1500
