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المؤلفون: Margaret A. Mohr, Tina Keshishian, Brennan A. Falcy, Blake J. Laham, Angela M. Wong, Paul E Micevych
المصدر: J Neuroendocrinol
مصطلحات موضوعية: Estradiol, Endocrine and Autonomic Systems, Endocrinology, Diabetes and Metabolism, Estrogen Receptor alpha, Hypothalamus, Estrogens, Article, Rats, Mice, Cellular and Molecular Neuroscience, Endocrinology, Astrocytes, Animals, Female, Sexual Maturation, Progesterone
الوصف: The development of estrogen positive feedback is a hallmark of female puberty. Both estrogen and progesterone signaling are required for the functioning of this neuroendocrine feedback loop but the physiological changes that underlie the emergence of positive feedback remain unknown. Only after puberty does estradiol (E2) facilitate progesterone synthesis in the rat female hypothalamus (neuroP), an event critical for positive feedback and the LH surge. We hypothesize that prior to puberty, these astrocytes have low levels of membrane estrogen receptor alpha (ERα), which is needed for facilitation of neuroP synthesis. Thus, we hypothesized that prepubertal astrocytes are unable to respond to E2 with increased neuroP synthesis due a lack of membrane ERα. To test this, hypothalamic tissues and enriched primary hypothalamic astrocyte cultures were acquired from pre-pubertal (postnatal week 3) and post-pubertal (week 8) female mice. E2-facilitated neuroP was measured in the hypothalamus pre- and post-puberty, and hypothalamic astrocyte responses were measured after treatment with E2. Prior to puberty, E2-facilitated neuroP synthesis did not occur in the hypothalamus, and mERα expression was low in hypothalamic astrocytes, but E2-facilitated neuroP synthesis in the rostral hypothalamus and mERα expression increased post-puberty. The increase in mERα expression in hypothalamic astrocytes corresponded with a post-pubertal increase in caveolin-1 protein, PKA phosphorylation, and a more rapid [Ca(2+)](i) flux in response to E2. Together, results from the present study indicate that E2-facilitated neuroP synthesis occurs in the rostral hypothalamus, develops during puberty, and corresponds to a post-pubertal increase in mERα levels in hypothalamic astrocytes.
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المؤلفون: Sabin A. Nettles, Katherine Warre-Cornish, Marc J. Tetel, Larry Denner, Lucia Dutan Polit, Deepak Srivastava, Cheryl F. Lichti, Kalpana D. Acharya
المصدر: J Neuroendocrinol
مصطلحات موضوعية: Agonist, medicine.medical_specialty, medicine.drug_class, Dopamine, Endocrinology, Diabetes and Metabolism, Hypothalamus, Nerve Tissue Proteins, 030209 endocrinology & metabolism, Interactome, Neuroprotection, Article, Energy homeostasis, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Animals, Protein Isoforms, Receptor, Progesterone, Neurons, Endocrine and Autonomic Systems, Chemistry, Mice, Inbred C57BL, Female, Receptors, Progesterone, Neural development, 030217 neurology & neurosurgery, Protein Binding, Signal Transduction, medicine.drug
الوصف: Neural progestin receptors (PR) function in reproduction, neural development, neuroprotection, learning, memory and the anxiety response. In the absence of progestins, PR can be activated by dopamine (DA) in the rodent hypothalamus to elicit female sexual behaviour. The present study investigated mechanisms of DA activation of PR by testing the hypothesis that proteins from DA-treated hypothalami interact with PR in the absence of progestins. Ovariectomised, oestradiol-primed mice were infused with a D1-receptor agonist, SKF38393 (SKF), into the third ventricle 30 minutes prior to death. Proteins from SKF-treated hypothalami were pulled-down with glutathione S-transferase-tagged mouse PR-A or PR-B and the interactomes were analysed by mass spectrometry. The largest functional group to interact with PR-A in a DA-dependent manner was synaptic proteins. To test the hypothesis that DA activation of PR regulates synaptic proteins, we developed oestradiol-induced PR-expressing hypothalamic-like neurones derived from human-induced pluripotent stem cells (hiPSCs). Similar to progesterone (P4), SKF treatment of hiPSCs increased synapsin1/2 expression. This SKF-dependent effect was blocked by the PR antagonist RU486, suggesting that PR are necessary for this DA-induced increase. The second largest DA-dependent PR-A protein interactome comprised metabolic regulators involved in glucose metabolism, lipid synthesis and mitochondrial energy production. Interestingly, hypothalamic proteins interacted with PR-A, but not PR-B, in an SKF-dependent manner, suggesting that DA promotes the interaction of multiple hypothalamic proteins with PR-A. These in vivo and in vitro results indicate novel mechanisms by which DA can differentially activate PR isoforms in the absence of P4 and provide a better understanding of ligand-independent PR activation in reproductive, metabolic and mental health disorders in women.
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المصدر: Journal of Neuroendocrinology. 34
مصطلحات موضوعية: Drug, medicine.medical_specialty, Neuroactive steroid, Allosteric modulator, Endocrine and Autonomic Systems, Chemistry, Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, Metabolite, Allopregnanolone, Pregnanolone, Neuroprotection, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Endocrinology, Internal medicine, medicine, Receptor, Neurosteroids, Progesterone, Drug metabolism, media_common
الوصف: Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and pathological conditions. In addition, its physiological and neuroprotective effects are also reported. Interestingly, the levels of this neuroactive steroid, as well as its effects, are sex-dimorphic, suggesting a possible gender medicine based on this neuroactive steroid for neurological disorders. However, allopregnanolone presents low bioavailability and extensive hepatic metabolism, limiting its use as a drug. Therefore, synthetic analogues or a different therapeutic strategy able to increase allopregnanolone levels have been proposed to overcome any pharmacokinetic issues.
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المؤلفون: Cecilia Jalabert, Kiran K. Soma, Chunqi Ma
المصدر: Journal of Neuroendocrinology. 33
مصطلحات موضوعية: Male, medicine.medical_specialty, Neuroactive steroid, Estrone, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Dehydroepiandrosterone, 030209 endocrinology & metabolism, Sexual Behavior, Animal, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Tandem Mass Spectrometry, Corticosterone, Internal medicine, medicine, Seasonal breeder, Animals, Androstenedione, Aromatase, Progesterone, Whole blood, Estradiol, biology, Endocrine and Autonomic Systems, Brain, Androgen, chemistry, biology.protein, Sparrows, 030217 neurology & neurosurgery, Chromatography, Liquid
الوصف: Steroids are secreted by the gonads and adrenal glands into the blood to modulate neurophysiology and behaviour. In addition, the brain can metabolise circulating steroids and synthesise steroids de novo. Songbirds show high levels of neurosteroid synthesis. In the present study, we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the measurement of 10 steroids in whole blood, plasma and microdissected brain tissue (1-2 mg) of song sparrows. Our assay is highly accurate, precise, specific and sensitive. Moreover, the liquid-liquid extraction is fast, simple and effective. We quantified steroids in the blood and brain of wild male song sparrows in both breeding and non-breeding seasons. As expected, systemic androgen levels were higher in the breeding season than in the non-breeding season. Brain androgens were detectable only in the breeding season; androstenedione and 5α-dihydrotestosterone levels were up to 20-fold higher in specific brain regions than in blood. Oestrogens were not detectable in blood in both seasons. Oestrone and 17β-oestradiol were detectable in brain in the breeding season only (up to 1.4 ng g-1 combined). Progesterone levels in several regions were higher in the non-breeding season than the breeding season, despite the lack of seasonal changes in systemic progesterone. Corticosterone levels in the blood were higher in the breeding season than in the non-breeding season but showed few seasonal differences in the brain. In general, the steroid levels presented here are lower than those in previous reports using immunoassays, because of the higher specificity of mass spectrometry. We conclude that (i) brain steroid levels can differ greatly from circulating steroid levels and (ii) brain steroid levels show region-specific seasonal patterns that are not a simple reflection of circulating steroid levels. This approach using ultrasensitive LC-MS/MS is broadly applicable to other species and allows steroid profiling in microdissected brain regions.
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المؤلفون: Marc Morissette, Thérèse Di Paolo, Katherine Coulombe, Andrée-Anne Poirier, Hend Jarras, Denis Soulet, Mélanie Bourque
المصدر: Journal of Neuroendocrinology. 32
مصطلحات موضوعية: Male, medicine.medical_specialty, Parkinson's disease, animal diseases, Endocrinology, Diabetes and Metabolism, Myenteric Plexus, 030209 endocrinology & metabolism, Inflammation, Neuroprotection, Immunomodulation, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Parkinsonian Disorders, Internal medicine, Glial Fibrillary Acidic Protein, medicine, Animals, Progesterone, Myenteric plexus, biology, Glial fibrillary acidic protein, Endocrine and Autonomic Systems, business.industry, Brain-Derived Neurotrophic Factor, Dopaminergic Neurons, MPTP, Dopaminergic, Brain, medicine.disease, nervous system diseases, Mice, Inbred C57BL, Disease Models, Animal, Neuroprotective Agents, nervous system, chemistry, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, biology.protein, medicine.symptom, business, 030217 neurology & neurosurgery, Neurotrophin
الوصف: Gastrointestinal symptoms appear in Parkinson's disease patients many years before motor symptoms, suggesting the implication of dopaminergic neurones of the gut myenteric plexus. Inflammation is also known to be increased in PD. We previously reported neuroprotection with progesterone in the brain of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and hypothesised that it also has neuroprotective and immunomodulatory activities in the gut. To test this hypothesis, we investigated progesterone administered to adult male C57BL/6 mice for 10 days and treated with MPTP on day 5. In an additional experiment, progesterone was administered for 5 days following MPTP treatment. Ilea were collected on day 10 of treatment and microdissected to isolate the myenteric plexus. Dopaminergic neurones were reduced by approximately 60% and pro-inflammatory macrophages were increased by approximately 50% in MPTP mice compared to intact controls. These changes were completely prevented by progesterone administered before and after MPTP treatment and were normalised by 8 mg kg-1 progesterone administered after MPTP. In the brain of MPTP mice, brain-derived neurotrophic peptide (BDNF) and glial fibrillary acidic protein (GFAP) were associated with progesterone neuroprotection. In the myenteric plexus, increased BDNF levels compared to controls were measured in MPTP mice treated with 8 mg kg-1 progesterone started post MPTP, whereas GFAP levels remained unchanged. In conclusion, the results obtained in the present study show neuroprotective and anti-inflammatory effects of progesterone in the myenteric plexus of MPTP mice that are similar to our previous findings in the brain. Progesterone is non-feminising and could be used for both men and women in the pre-symptomatic stages of the disease.
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7دورية أكاديمية
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8دورية أكاديمية
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المؤلفون: Laura Garay, M. C. Gonzalez Deniselle, Rachida Guennoun, Juan José Poderoso, Michael Schumacher, Maria Meyer, Gisella Gargiulo-Monachelli, Maria Cecilia Carreras, A. F. De Nicola
المصدر: CONICET Digital (CONICET)
Consejo Nacional de Investigaciones Científicas y Técnicas
instacron:CONICETمصطلحات موضوعية: medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Encephalomyelitis, Autoimmune, Experimental, Neuroactive steroid, Endocrinology, Diabetes and Metabolism, Neurociencias, Respiratory chain, Biology, Neuroprotection, Proinflammatory cytokine, Mice, Cellular and Molecular Neuroscience, Endocrinology, Internal medicine, medicine, Animals, Progesterone, Neuroinflammation, NEUROPROTECTION, Endocrine and Autonomic Systems, WOBBLER MOUSE, Neurodegeneration, Experimental autoimmune encephalomyelitis, Neurodegenerative Diseases, PROGESTERONE, purl.org/becyt/ford/3.1 [https], medicine.disease, ANTI-INFLAMMATORY EFFECTS, Nitric oxide synthase, Medicina Básica, Disease Models, Animal, Neuroprotective Agents, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, biology.protein, purl.org/becyt/ford/3 [https], Progestins
الوصف: Progesterone is a neuroprotective, promyelinating and antiinflammatory factor for the nervous system. Here we discuss progesterone effects in models of motoneuron degeneration and neuroinflammation. In neurodegeneration of the Wobbler mouse, a subset of spinal cord motoneurons showed increased activity of nitric oxide synthase (NOS), increased intramitochondrial NOS, decreased activity of respiratory chain complexes and decreased activity and protein expression of Mnsuperoxide dismutase type 2 (MnSOD2). Clinically, Wobblers suffered several degrees of motor impairment. Progesterone treatment restored the expression of neuronal markers, decreased the activity of NOS and enhanced complex I respiratory activity and MnSOD2. Long-term treatment with progesterone increased muscle strength, biceps weight and survival. Collectively, these data supported that progesterone prevented neurodegeneration. To study progesterone effects in neuroinflammation, we employed mice with experimental autoimmune encephalomyelitis (EAE). EAE mice spinal cord showed increased mRNA levels of the inflammatory mediators tumour necrosis factor α (TNFα) and its receptor TNFR1, the microglial marker CD11b, iNOS and the toll-like receptor 4 (TLR4). Progesterone pretreatment of EAE mice blocked the proinflammatory mediators, decreased Iba1+ microglial cells and attenuated clinical signs of EAE. Therefore, reactive glial cells became targets of progesterone anti-inflammatory effects. These results open the ground for testing the usefulness of neuroactive steroids for neurological disorders. Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Gonzalez Deniselle, Maria Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Garay, Laura Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Gargiulo Monachelli, Gisella Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Guennoun, Rachida. Inserm; Francia. Universite Paris Sud; Francia Fil: Schumacher, M.. Inserm; Francia. Universite Paris Sud; Francia Fil: Carreras, Maria Cecilia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentina Fil: Poderoso, Juan José. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentina
وصف الملف: application/pdf
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المؤلفون: Sergei Musatov, Sonoko Ogawa, Anders Ågmo, Thierry Spiteri, Eelke M.S. Snoeren, Edwards Antonio‐Cabrera, Donald W. Pfaff
المصدر: Journal of Neuroendocrinology. 27:803-818
مصطلحات موضوعية: Male, endocrine system, medicine.medical_specialty, Lordosis, Injections, Subcutaneous, Endocrinology, Diabetes and Metabolism, Estrogen receptor, Biology, Amygdala, Sexual Behavior, Animal, Cellular and Molecular Neuroscience, Endocrinology, Internal medicine, medicine, Animals, RNA, Small Interfering, Social Behavior, Progesterone, Endocrine and Autonomic Systems, Estrogen Receptor alpha, Septal nuclei, Estrogens, medicine.disease, VDP::Matematikk og Naturvitenskap: 400::Zoologiske og botaniske fag: 480::Zoofysiologi og komparativ fysiologi: 483, Housing, Animal, Preoptic Area, Rats, Preoptic area, Stria terminalis, medicine.anatomical_structure, Ventromedial nucleus of the hypothalamus, Ventromedial Hypothalamic Nucleus, VDP::Mathematics and natural science: 400::Zoology and botany: 480::Zoophysiology and comparative physiology: 483, Female, Septal Nuclei, Estrogen receptor alpha
الوصف: The present study investigated the role of oestrogen receptor (ER)α in the ventromedial nucleus of the hypothalamus (VMN), the preoptic area (POA), the medial amygdala (MePD) and the bed nucleus of stria terminalis (BNST) in sociosexual behaviour in female rats. This was conducted in two sets of experiments, with the VMN and POA investigated in the first set, and the MePD and BNST in the second set. The VMN and POA received intense projections from the MePD and BNST. We used a short hairpin RNA encoded within an adeno‐associated viral vector directed against the gene for ERα to reduce the number of ERα in the VMN or POA (first set of experiments) or in the BNST or MePD (second set of experiments) in female rats. The rats were housed in groups of four ovariectomised females and three males in a seminatural environment for 8 days. Compared with traditional test set‐ups, the seminatural environment provides an arena in which the rats can express their full behavioural repertoire, which allowed us to investigate multiple aspects of social and sexual behaviour in groups of rats. Behavioural observation was performed after oestrogen and progesterone injections. A reduction of ERα expression in the VMN or POA diminished the display of paracopulatory behaviours and lordosis responses compared to controls, whereas the lordosis quotient remained unaffected. This suggests that ERα in the VMN and POA play an important role in intrinsic sexual motivation. The reduction in ERα did not affect the social behaviour of the females, although the males sniffed and pursued the females with reduced ERα less than the controls. This suggests that the ERα in the VMN and POA is involved in the regulation of sexual attractiveness of females. The ERα in the MePD and BNST, on the other hand, plays no role in sociosexual behaviour.
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