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Clinically Relevant Progestins Regulate Neurogenic and Neuroprotective Responses in Vitro and in Vivo

Program in Neuroscience, University of Southern California, School of Pharmacy Pharmaceutical Sciences Center, Los Angeles, California 90033, USA.
Endocrinology (Impact Factor: 4.5). 10/2010; 151(12):5782-94. DOI: 10.1210/en.2010-0005
Source: PubMed

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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    • "In addition to its use in reproduction, Nestorone has shown strong effects in the nervous system. Thus, Nestorone provides neuroprotection against cerebral ischemia, increases adult rat neural progenitor cell proliferation, enhances myelin repair in a chemical demyelination model, increases the brain regenerative capacity, and constitutes an effective treatment for experimental autoimmune encephalomyelitis (EAE) and for stimulating myelin regeneration after cuprizone-induced demyelination (Liu et al., 2010, 2012; Hussain et al., 2011; Garay et al., 2014; El Etr et al., 2015). Regarding its mechanism of action in the nervous system, it is likely that central effects of Nestorone require the PR. "
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    ABSTRACT: Wobbler mutant mice suffer from progressive motoneuron degeneration and glial cell reactivity in the spinal cord. To prevent development of these abnormalities, we employed Nestorone, a high affinity progesterone receptor agonist endowed with neuroprotective, promyelinating and anti-inflammatory activities in experimental brain ischemia, preventing neuroinflammation and chemical degeneration. Five month old Wobbler mice (wr -/ wr-) received s.c. injections of 200 μg /day /mouse of Nestorone in vegetable oil or vehicle for 10 days. Control NFR/NFR mice (background strain for Wobbler) received vehicle only. Vehicle-treated Wobblers showed typical spinal cord abnormalities, such as vacuolated motoneurons, decreased immunoreactive choline-acetyltransferase, decreased expression of glutamine synthase, increased glial fibrillary acidic protein positive (GFAP) astrogliosis and curved digits in forelimbs. These cell-specific abnormalities were normalized in Nestorone treated Wobblers. In addition, vehicle-treated Wobblers showed Iba1+ microgliosis, high expression of the microglial marker CD11b mRNA and up-regulation of the proinflammatory markers TNFα and iNOS mRNAs. In Nestorone-treated Wobblers, Iba1+ microgliosis subsided, whereas CD11b, TNFα and iNOS mRNAs were down-regulated. NFκB mRNA was increased in Wobbler spinal cord and decreased by Nestorone, whereas expression of its inhibitor IκBα was increased in Nestorone-treated Wobblers compared to control mice and vehicle-treated Wobblers. In conclusion, our results showed that Nestorone restraining effects on proinflammatory mediators, microgliosis and astrogliosis may support neurons in their resistance against degenerative processes.
    Full-text · Article · Sep 2015 · Neuroscience
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    • "In addition to its use in reproduction, Nestorone has shown strong effects in the nervous system. Thus, Nestorone provides neuroprotection against cerebral ischemia, increases adult rat neural progenitor cell proliferation, enhances myelin repair in a chemical demyelination model, increases the brain regenerative capacity, and constitutes an effective treatment for experimental autoimmune encephalomyelitis (EAE) and for stimulating myelin regeneration after cuprizone-induced demyelination (Liu et al., 2010, 2012; Hussain et al., 2011; Garay et al., 2014; El Etr et al., 2015). Regarding its mechanism of action in the nervous system, it is likely that central effects of Nestorone require the PR. "
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    ABSTRACT: The anti-inflammatory effects of progesterone have been increasingly recognized in several neuropathological models, including spinal cord inflammation. In the present investigation, we explored the regulation of proinflammatory factors and enzymes by progesterone at several time points after spinal cord injury (SCI) in male rats. We also demonstrated the role of the progesterone receptor (PR) in inhibiting inflammation and reactive gliosis, and in enhancing the survival of oligodendrocyte progenitors cells (OPC) in injured PR knockout (PRKO) mice receiving progesterone. First, after SCI in rats, progesterone greatly attenuated the injury-induced hyperexpression of the mRNAs of interleukin 1β (IL1β), IL6, tumor necrosis factor alpha (TNFα), inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), all involved in oligodendrocyte damage. Second, the role of the PR was investigated in PRKO mice after SCI, in which progesterone failed to reduce the high expression of IL1β, IL6, TNFα and IκB-α mRNAs, the latter being considered an index of reduced NF-κB transactivation. These effects occurred in a time framework coincident with a reduction in the astrocyte and microglial responses. In contrast to wild-type mice, progesterone did not increase the density of OPC and did not prevent apoptotic death of these cells in PRKO mice. Our results support a role of PR in: (a) the anti-inflammatory effects of progesterone; (b) the modulation of astrocyte and microglial responses and (c) the prevention of OPC apoptosis, a mechanism that would enhance the commitment of progenitors to the remyelination pathway in the injured spinal cord.
    Full-text · Article · Sep 2015 · The Journal of steroid biochemistry and molecular biology
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    • "such beneficial effects and can even become harmful for neural cells (Liu et al., 2010; Hussain et al., 2011). Indeed, in contrast to natural progesterone and Nestorone, the synthetic 17-OH progesterone derivative MPA was inefficient in stimulating the formation of new myelin sheaths in organotypic cultures of cerebellar slices (Hussain et al., 2011). "
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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.
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