Clinically Relevant Progestins Regulate Neurogenic and Neuroprotective Responses in Vitro and in Vivo
ABSTRACT Previously, we demonstrated that progesterone (P(4)) promoted adult rat neural progenitor cell (rNPC) proliferation with concomitant regulation of cell-cycle gene expression via the P(4) receptor membrane component/ERK pathway. Here, we report the efficacy of seven clinically relevant progestins alone or in combination with 17β-estradiol (E(2)) on adult rNPC proliferation and hippocampal cell viability in vitro and in vivo. In vitro analyses indicated that P(4), norgestimate, Nestorone, norethynodrel, norethindrone, and levonorgestrel (LNG) significantly increased in rNPC proliferation, whereas norethindrone acetate was without effect, and medroxyprogesterone acetate (MPA) inhibited rNPC proliferation. Proliferative progestins in vitro were also neuroprotective. Acute in vivo exposure to P(4) and Nestorone significantly increased proliferating cell nuclear antigen and cell division cycle 2 expression and total number of hippocampal 5-bromo-2-deoxyuridine (BrdU)-positive cells, whereas LNG and MPA were without effect. Mechanistically, neurogenic progestins required activation of MAPK to promote proliferation. P(4), Nestorone, and LNG significantly increased ATP synthase subunit α (complex V, subunit α) expression, whereas MPA was without effect. In combination with E(2), P(4), Nestorone, LNG, and MPA significantly increased BrdU incorporation. However, BrdU incorporation induced by E(2) plus LNG or MPA was paralleled by a significant increase in apoptosis. A rise in Bax/Bcl-2 ratio paralleled apoptosis induced by LNG and MPA. With the exception of P(4), clinical progestins antagonized E(2)-induced rise in complex V, subunit α. These preclinical translational findings indicate that the neurogenic response to clinical progestins varies dramatically. Progestin impact on the regenerative capacity of the brain has clinical implications for contraceptive and hormone therapy formulations prescribed for pre- and postmenopausal women.
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ABSTRACT: Progesterone is well known as a female reproductive hormone and in particular for its role in uterine receptivity, implantation, and the maintenance of pregnancy. However, neuroendocrine research over the past decades has established that progesterone has multiple functions beyond reproduction. Within the nervous system, its neuromodulatory and neuroprotective effects are much studied. Although progesterone has been shown to also promote myelin repair, its influence and that of other steroids on myelination and remyelination is relatively neglected. Reasons for this are that hormonal influences are still not considered as a central problem by most myelin biologists, and that neuroendocrinologists are not sufficiently concerned with the importance of myelin in neuron functions and viability. The effects of progesterone in the nervous system involve a variety of signaling mechanisms. The identification of the classical intracellular progesterone receptors as therapeutic targets for myelin repair suggests new health benefits for synthetic progestins, specifically designed for contraceptive use and hormone replacement therapies. There are also major advantages to use natural progesterone in neuroprotective and myelin repair strategies, because progesterone is converted to biologically active metabolites in nervous tissues and interacts with multiple target proteins. The delivery of progesterone however represents a challenge because of its first-pass metabolism in digestive tract and liver. Recently, the intranasal route of progesterone administration has received attention for easy and efficient targeting of the brain. Progesterone in the brain is derived from the steroidogenic endocrine glands or from local synthesis by neural cells. Stimulating the formation of endogenous progesterone is currently explored as an alternative strategy for neuroprotection, axonal regeneration, and myelin repair.Frontiers in Neuroscience 02/2012; 6:10. DOI:10.3389/fnins.2012.00010
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ABSTRACT: The impact of clinical progestins used in contraception and hormone therapies on the metabolic capacity of the brain has long-term implications for neurological health in pre- and postmenopausal women. Previous analyses indicated that progesterone and 17β-estradiol (E2) sustain and enhance brain mitochondrial energy-transducing capacity. Herein we determined the impact of the clinical progestin, medroxyprogesterone acetate (MPA), on glycolysis, oxidative stress, and mitochondrial function in brain. Ovariectomized female rats were treated with MPA, E2, E2+MPA, or vehicle with ovary-intact rats serving as a positive control. MPA alone and MPA plus E2 resulted in diminished mitochondrial protein levels for pyruvate dehydrogenase, cytochrome oxidase, ATP synthase, manganese-superoxide dismutase, and peroxiredoxin V. MPA alone did not rescue the ovariectomy-induced decrease in mitochondrial bioenergetic function, whereas the coadministration of E2 and MPA exhibited moderate efficacy. However, the coadministration of MPA was detrimental to antioxidant defense, including manganese-superoxide dismutase activity/expression and peroxiredoxin V expression. Accumulated lipid peroxides were cleared by E2 treatment alone but not in combination with MPA. Furthermore, MPA abolished E2-induced enhancement of mitochondrial respiration in primary cultures of the hippocampal neurons and glia. Collectively these findings indicate that the effects of MPA differ significantly from the bioenergetic profile induced by progesterone and that, overall, MPA induced a decline in glycolytic and oxidative phosphorylation protein and activity. These preclinical findings on the basis of acute exposure to MPA raise concerns regarding neurological health after chronic use of MPA in contraceptive and hormone therapy.Endocrinology 02/2011; 152(2):556-67. DOI:10.1210/en.2010-1061
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ABSTRACT: Despite decades of laboratory research and clinical trials, a safe and effective treatment for traumatic brain injury has yet to reach clinical practice. The failure is due in part to the prevalence of a reductionist philosophy and research praxis that targets a single receptor mechanism, gene, or brain locus. This approach fails to account for the fact that traumatic brain injury is a very complex disease caused by a cascade of systemic toxic events in the brain and throughout the body. Attention is now turning to pleiotropic drugs that act on multiple genomic, proteomic, and metabolic pathways to enhance morphological and functional outcomes after brain injury. Of the agents now in clinical trial, the neurosteroid progesterone appears to hold considerable promise. Many still assume that progesterone is "just a female hormone" with limited, if any, neuroprotective properties, but this view is outdated. This review will survey the evidence that progesterone has salient pleiotropic properties as a neuroprotective agent in a variety of central nervous system injury models. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.Neuroscience 04/2011; 191:101-6. DOI:10.1016/j.neuroscience.2011.04.013