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[PMID]:28471529
[Au] Autor:Trivisano M; Lucchi C; Rustichelli C; Terracciano A; Cusmai R; Ubertini GM; Giannone G; Bertini ES; Vigevano F; Gecz J; Biagini G; Specchio N
[Ad] Endereço:Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
[Ti] Título:Reduced steroidogenesis in patients with PCDH19-female limited epilepsy.
[So] Source:Epilepsia;58(6):e91-e95, 2017 06.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Patients affected by protocadherin 19 (PCDH19)-female limited epilepsy (PCDH19-FE) present a remarkable reduction in allopregnanolone blood levels. However, no information is available on other neuroactive steroids and the steroidogenic response to hormonal stimulation. For this reason, we evaluated allopregnanolone, pregnanolone, and pregnenolone sulfate by liquid chromatographic procedures coupled with electrospray tandem mass spectrometry in 12 unrelated patients and 15 age-matched controls. We also tested cortisol, estradiol, progesterone, and 17OH-progesterone using standard immunoassays. Apart from estradiol and progesterone, all the considered hormones were evaluated in basal condition and after stimulation with adrenocorticotropic hormone (ACTH). A generalized decrease in blood levels of almost all measured neuroactive steroids was found. When considering sexual development, cortisol and pregnenolone sulfate basal levels were significantly reduced in postpubertal girls affected by PCDH19-FE. Of interest, ACTH administration did not recover pregnenolone sulfate serum levels but restored cortisol to control levels. In prepubertal girls with PCDH19-FE, by challenging adrenal function with ACTH we disclosed defects in the production of cortisol, pregnenolone sulfate, and 17OH-progesterone, which were not apparent in basal condition. These findings point to multiple defects in peripheral steroidogenesis associated with and potentially relevant to PCDH19-FE. Some of these defects could be addressed by stimulating adrenocortical activity.
[Mh] Termos MeSH primário: Caderinas/genética
Epilepsia/sangue
Epilepsia/genética
Doenças Genéticas Ligadas ao Cromossomo X/sangue
Doenças Genéticas Ligadas ao Cromossomo X/genética
Hormônios Esteroides Gonadais/sangue
Deficiência Intelectual/sangue
Deficiência Intelectual/genética
Pregnanolona/sangue
Pregnanolona/deficiência
Pregnenolona/sangue
[Mh] Termos MeSH secundário: 17-alfa-Hidroxiprogesterona/sangue
Adolescente
Hormônio Adrenocorticotrópico/farmacologia
Síndrome Adrenogenital/sangue
Estudos de Casos e Controles
Criança
Pré-Escolar
Análise Mutacional de DNA
Estradiol/sangue
Feminino
Seres Humanos
Hidrocortisona/sangue
Progesterona/sangue
Estudos Prospectivos
Puberdade Precoce/sangue
Puberdade Precoce/genética
Valores de Referência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cadherins); 0 (Gonadal Steroid Hormones); 0 (PCDH19 protein, human); 04Y4D91RG0 (pregnenolone sulfate); 4G7DS2Q64Y (Progesterone); 4TI98Z838E (Estradiol); 68-96-2 (17-alpha-Hydroxyprogesterone); 73R90F7MQ8 (Pregnenolone); 9002-60-2 (Adrenocorticotropic Hormone); BXO86P3XXW (Pregnanolone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180107
[Lr] Data última revisão:
180107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13772


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[PMID]:28743598
[Au] Autor:Ebihara K; Fujiwara H; Awale S; Dibwe DF; Araki R; Yabe T; Matsumoto K
[Ad] Endereço:Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
[Ti] Título:Decrease in endogenous brain allopregnanolone induces autism spectrum disorder (ASD)-like behavior in mice: A novel animal model of ASD.
[So] Source:Behav Brain Res;334:6-15, 2017 09 15.
[Is] ISSN:1872-7549
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABA receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1mg/kg, i.p.) and methylphenidate (MPH: 2.5mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABA receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD.
[Mh] Termos MeSH primário: Androstanos
Transtorno do Espectro Autista/metabolismo
Encéfalo/metabolismo
Modelos Animais de Doenças
Pregnanolona/deficiência
[Mh] Termos MeSH secundário: Inibidores de 5-alfa Redutase/farmacologia
Animais
Ansiedade/metabolismo
Transtorno do Espectro Autista/tratamento farmacológico
Transtorno do Espectro Autista/psicologia
Encéfalo/efeitos dos fármacos
Medo/fisiologia
Feminino
Asseio Animal/fisiologia
Aprendizagem/fisiologia
Masculino
Memória/fisiologia
Metilfenidato/farmacologia
Camundongos Endogâmicos ICR
Psicotrópicos/farmacologia
Caracteres Sexuais
Comportamento Social
Comportamento Estereotipado/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (5-alpha Reductase Inhibitors); 0 (Androstanes); 0 (Psychotropic Drugs); 0 (SKF 105111); 207ZZ9QZ49 (Methylphenidate); BXO86P3XXW (Pregnanolone)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE


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[PMID]:28951257
[Au] Autor:Meyer M; Garay LI; Kruse MS; Lara A; Gargiulo-Monachelli G; Schumacher M; Guennoun R; Coirini H; De Nicola AF; Gonzalez Deniselle MC
[Ad] Endereço:Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina.
[Ti] Título:Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration.
[So] Source:J Steroid Biochem Mol Biol;174:201-216, 2017 Nov.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by progressive death of motoneurons. The Wobbler (WR) mouse is a preclinical model sharing neuropathological similarities with human ALS. We have shown that progesterone (PROG) prevents the progression of motoneuron degeneration. We now studied if allopregnanolone (ALLO), a reduced metabolite of PROG endowed with gabaergic activity, also prevents WR neuropathology. Sixty-day old WRs remained untreated or received two steroid treatment regimens in order to evaluate the response of several parameters during early or prolonged steroid administration. ALLO was administered s.c. daily for 5days (4mg/kg) or every other day for 32days (3, 3mg/kg), while another group of WRs received a 20mg PROG pellet s.c. for 18 or 60days. ALLO administration to WRs increased ALLO serum levels without changing PROG and 5 alpha dihydroprogesterone (5α-DHP), whereas PROG treatment increased PROG, 5α-DHP and ALLO. Untreated WRs showed higher basal levels of serum 5α-DHP than controls. In the cervical spinal cord we studied markers of oxidative stress or associated to trophic responses. These included nitric oxide synthase (NOS) activity, motoneuron vacuolation, MnSOD immunoreactivity (IR), brain derived neurotrophic factor (BDNF) and TrkB mRNAs, p75 neurotrophin receptor (p75NTR) and, cell survival or death signals such as pAKT and the stress activated kinase JNK. Untreated WRs showed a reduction of MnSOD-IR and BDNF/TrkB mRNAs, associated to high p75NTR in motoneurons, neuronal and glial NOS hyperactivity and neuronal vacuolation. Also, low pAKT, mainly in young WRs, and a high pJNK in the old stage characterized WRs spinal cord. Except for MnSOD and BDNF, these alterations were prevented by an acute ALLO treatment, while short-term PROG elevated MnSOD. Moreover, after chronic administration both steroids enhanced MnSOD-IR and BDNF mRNA, while attenuated pJNK and NOS in glial cells. Long-term PROG also increased pAKT and reduced neuronal NOS, parameters not modulated by chronic ALLO. Clinically, both steroids improved muscle performance. Thus, ALLO was able to reduce neuropathology in this model. Since high oxidative stress activates p75NTR and pJNK in neurodegeneration, steroid reduction of these molecules may provide adequate neuroprotection. These data yield the first evidence that ALLO, a gabaergic neuroactive steroid, brings neuroprotection in a model of motoneuron degeneration.
[Mh] Termos MeSH primário: Degeneração Neural/tratamento farmacológico
Fármacos Neuroprotetores/uso terapêutico
Pregnanolona/uso terapêutico
[Mh] Termos MeSH secundário: Esclerose Amiotrófica Lateral
Animais
Fator Neurotrófico Derivado do Encéfalo/genética
Colina O-Acetiltransferase/metabolismo
Modelos Animais de Doenças
Feminino
Masculino
Camundongos
Neurônios Motores/efeitos dos fármacos
Neurônios Motores/patologia
Degeneração Neural/genética
Degeneração Neural/metabolismo
Fármacos Neuroprotetores/sangue
Fármacos Neuroprotetores/farmacologia
Óxido Nítrico Sintase/metabolismo
Pregnanolona/sangue
Pregnanolona/farmacologia
Progesterona/sangue
Progesterona/farmacologia
Progesterona/uso terapêutico
Receptor trkB/genética
Receptores de Fator de Crescimento Neural/metabolismo
Medula Espinal/metabolismo
Medula Espinal/patologia
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Brain-Derived Neurotrophic Factor); 0 (Neuroprotective Agents); 0 (Receptors, Nerve Growth Factor); 0 (TNFRSF16 protein, mouse); 4G7DS2Q64Y (Progesterone); BXO86P3XXW (Pregnanolone); EC 1.14.13.39 (Nitric Oxide Synthase); EC 1.15.1.1 (Superoxide Dismutase); EC 2.3.1.6 (Choline O-Acetyltransferase); EC 2.7.10.1 (Receptor, trkB)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE


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[PMID]:28890368
[Au] Autor:de Mello Martins AGG; Allegretta G; Unteregger G; Haupenthal J; Eberhard J; Hoffmann M; van der Zee JA; Junker K; Stöckle M; Müller R; Hartmann RW; Ohlmann CH
[Ad] Endereço:Department of Drug Design and Optimization (DDOP), Helmholtz Institute for Pharmaceutical Research Saarland, Campus E8.1, 66123 Saarbrücken, Germany.
[Ti] Título:CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3ß,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone.
[So] Source:J Steroid Biochem Mol Biol;174:183-191, 2017 Nov.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:CYP17A1-independent intratumoral steroid hormone synthesis is regarded as one possible explanation for resistance to treatment with the CYP17-inhibitor Abiraterone (Abi). The aim of our study was therefore to investigate the steroid metabolism of prostate cancer cells under serum starvation and the effects of Abi treatment. We assessed steroid metabolism in a panel of prostate cancer cells under serum starvation by radioactivity detector-coupled HPLC and HPLC-ESI-ToF-mass spectrometry after treatment with pregnenolone, progesterone and allopregnanolone. We further evaluated the effects of Abi on steroid metabolism of testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA) by enzyme immunoassays (EIAs). Androgen-responsive cell lines metabolized pregnenolone primarily to mitogenic steroid 5α-pregnan-3ß,6α-diol-20-one under serum starvation. Co-administration of Abi lead to detectable concentrations of the Abi metabolite Δ -Abi (D4A), known to inhibit enzymes other than CYP17A1 in steroid metabolism. In addition, co-administration of Abi abrogated pregnenolone metabolism and resulted in a CYP17A1-independent significant increase of DHEA (13- to >100-fold) and DHT (2.5-fold) in androgen-responsive cells. Our results demonstrate the CYP17A1-independent formation of 5α-pregnan-3ß,6α-diol-20-one by androgen-responsive prostate cancer cells under serum starvation and its inhibition by Abi. Its metabolism from pregnenolone suggests a major steroidogenesis shift in these cells, hinting at a neuroendocrine transdifferentiation phenomenon. The marked increase of DHEA levels by Abi resembles the steroidogenic pathways in nervous tissue, in a manner that precludes CYP17A1 activity. To which extent these processes are responsible or involved in the development of resistance to Abi, needs to be further elucidated.
[Mh] Termos MeSH primário: Pregnanolona/análogos & derivados
Neoplasias da Próstata/metabolismo
Esteroide 17-alfa-Hidroxilase/metabolismo
[Mh] Termos MeSH secundário: Androgênios/metabolismo
Androstenos/farmacologia
Linhagem Celular Tumoral
Hormônios Esteroides Gonadais/metabolismo
Seres Humanos
Masculino
Pregnanolona/metabolismo
Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgens); 0 (Androstenes); 0 (Gonadal Steroid Hormones); 570-78-5 (pregnan-3,6-diol-20-one); BXO86P3XXW (Pregnanolone); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); G819A456D0 (abiraterone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE


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[PMID]:28779545
[Au] Autor:Rosenthal ES; Claassen J; Wainwright MS; Husain AM; Vaitkevicius H; Raines S; Hoffmann E; Colquhoun H; Doherty JJ; Kanes SJ
[Ad] Endereço:Massachusetts General Hospital, Boston, MA.
[Ti] Título:Brexanolone as adjunctive therapy in super-refractory status epilepticus.
[So] Source:Ann Neurol;82(3):342-352, 2017 Sep.
[Is] ISSN:1531-8249
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Super-refractory status epilepticus (SRSE) is a life-threatening form of status epilepticus that continues or recurs despite 24 hours or more of anesthetic treatment. We conducted a multicenter, phase 1/2 study in SRSE patients to evaluate the safety and tolerability of brexanolone (USAN; formerly SAGE-547 Injection), a proprietary, aqueous formulation of the neuroactive steroid, allopregnanolone. Secondary objectives included pharmacokinetic assessment and open-label evaluation of brexanolone response during and after anesthetic third-line agent (TLA) weaning. METHODS: Patients receiving TLAs for SRSE control were eligible for open-label, 1-hour brexanolone loading infusions, followed by maintenance infusion. After 48 hours of brexanolone infusion, TLAs were weaned during brexanolone maintenance. After 4 days, the brexanolone dose was tapered. Safety and functional status were assessed over 3 weeks of follow-up. RESULTS: Twenty-five patients received open-label study drug. No serious adverse events (SAEs) were attributable to study drug, as determined by the Safety Review Committee. Sixteen patients (64%) experienced ≥1 SAE. Six patient deaths occurred, all deemed related to underlying medical conditions. Twenty-two patients underwent ≥1 TLA wean attempt. Seventeen (77%) met the response endpoint of weaning successfully off TLAs before tapering brexanolone. Sixteen (73%) were successfully weaned off TLAs within 5 days of initiating brexanolone infusion without anesthetic agent reinstatement in the following 24 hours. INTERPRETATION: In an open-label cohort of limited size, brexanolone demonstrated tolerability among SRSE patients of heterogeneous etiologies and was associated with a high rate of successful TLA weaning. The results suggest the possible development of brexanolone as an adjunctive therapy for SRSE requiring pharmacological coma for seizure control. Ann Neurol 2017;82:342-352.
[Mh] Termos MeSH primário: Anticonvulsivantes/uso terapêutico
Pregnanolona/uso terapêutico
Estado Epiléptico/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Anticonvulsivantes/efeitos adversos
Criança
Feminino
Seres Humanos
Masculino
Meia-Idade
Pregnanolona/efeitos adversos
Recidiva
Estudos Retrospectivos
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Anticonvulsants); BXO86P3XXW (Pregnanolone)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170806
[St] Status:MEDLINE
[do] DOI:10.1002/ana.25008


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[PMID]:28753313
[Au] Autor:Martinez Botella G; Salituro FG; Harrison BL; Beresis RT; Bai Z; Blanco MJ; Belfort GM; Dai J; Loya CM; Ackley MA; Althaus AL; Grossman SJ; Hoffmann E; Doherty JJ; Robichaud AJ
[Ad] Endereço:Sage Therapeutics, Inc. 215 First Street, Cambridge, Massachusetts 02142, United States.
[Ti] Título:Neuroactive Steroids. 2. 3α-Hydroxy-3ß-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5ß-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid) Receptor.
[So] Source:J Med Chem;60(18):7810-7819, 2017 Sep 28.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABA receptors. Herein, we report new SAR insights in a series of 5ß-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3ß-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5ß-pregnan-20-one (SAGE-217, 3), a potent GABA receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound 3 has completed a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial and is currently being studied in parallel phase 2 clinical trials for the treatment of postpartum depression (PPD), major depressive disorder (MDD), and essential tremor (ET).
[Mh] Termos MeSH primário: Regulação Alostérica/efeitos dos fármacos
Agonistas de Receptores de GABA-A/química
Agonistas de Receptores de GABA-A/farmacologia
Pregnanolona/análogos & derivados
Receptores de GABA-A/metabolismo
[Mh] Termos MeSH secundário: Animais
Depressão Pós-Parto/tratamento farmacológico
Transtorno Depressivo Maior/tratamento farmacológico
Feminino
Agonistas de Receptores de GABA-A/farmacocinética
Camundongos
Pregnanolona/química
Pregnanolona/farmacocinética
Pregnanolona/farmacologia
Pirazóis/química
Pirazóis/farmacocinética
Pirazóis/farmacologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GABA-A Receptor Agonists); 0 (Pyrazoles); 0 (Receptors, GABA-A); 32695-80-0 (pregnane-20-one); BXO86P3XXW (Pregnanolone)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170729
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00846


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[PMID]:28476183
[Au] Autor:Syan SK; Minuzzi L; Costescu D; Smith M; Allega OR; Coote M; Hall GBC; Frey BN
[Ad] Endereço:MiNDS Neuroscience Graduate Program, McMaster University, Hamilton, Ontario, Canada; Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
[Ti] Título:Influence of endogenous estradiol, progesterone, allopregnanolone, and dehydroepiandrosterone sulfate on brain resting state functional connectivity across the menstrual cycle.
[So] Source:Fertil Steril;107(5):1246-1255.e4, 2017 May.
[Is] ISSN:1556-5653
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To [1] study brain resting state functional connectivity (Rs-FC) in a well-characterized sample of healthy women in the mid-follicular and late luteal phases of the menstrual cycle; and [2] examine the correlation between endogenous E , P, allopregnanolone, and DHEAS and patterns of Rs-FC across the menstrual cycle. DESIGN: We studied the Rs-FC of the default mode network, salience network, meso-paralimbic network, fronto-parietal network, visual network, and sensorimotor network in the mid-follicular and late luteal phases. Serum levels of E , P, allopregnanolone, and DHEAS were correlated to patterns of functional connectivity. SETTING: University medical center. PATIENT(S): Twenty-five healthy women with regular menstrual cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Functional connectivity of key brain networks at rest and correlations of hormones to Rs-FC in the mid-follcuar and late luteal menstrual phases. RESULT(S): There were no differences in Rs-FC between the mid-follicular and late luteal menstrual phases using either independent component analysis or seed-based analysis. However, specific correlations between each hormone and patterns of functional connectivity were found in both menstrual cycle phases. CONCLUSION(S): It seems that the association between female sex hormones and brain Rs-FC is menstrual cycle phase-dependent. Future studies should examine the cognitive and behavioral correlates of this association in regularly cycling women.
[Mh] Termos MeSH primário: Encéfalo/fisiologia
Hormônios Esteroides Gonadais/sangue
Ciclo Menstrual/fisiologia
Rede Nervosa/fisiologia
Descanso/fisiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Conectoma/métodos
Sulfato de Desidroepiandrosterona/sangue
Estradiol/sangue
Feminino
Seres Humanos
Meia-Idade
Plasticidade Neuronal/fisiologia
Pregnanolona/sangue
Progesterona/sangue
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gonadal Steroid Hormones); 4G7DS2Q64Y (Progesterone); 4TI98Z838E (Estradiol); 57B09Q7FJR (Dehydroepiandrosterone Sulfate); BXO86P3XXW (Pregnanolone)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170507
[St] Status:MEDLINE


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[PMID]:28416442
[Au] Autor:Lévesque M; Herrington R; Leclerc L; Rogawski MA; Avoli M
[Ad] Endereço:Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal H3A 2B4, Qc, Canada.
[Ti] Título:Allopregnanolone decreases interictal spiking and fast ripples in an animal model of mesial temporal lobe epilepsy.
[So] Source:Neuropharmacology;121:12-19, 2017 Jul 15.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The objective of this study was to characterize the impact of allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABA receptors, on interictal spikes and high-frequency oscillations (ripples: 80-200 Hz, fast ripples: 250-500 Hz) in the pilocarpine model of mesial temporal lobe epilepsy. Seven out of 25 Sprague-Dawley rats experiencing 1 h of pilocarpine-induced status epilepticus (SE) began treatment with allopregnanolone (9.6-12.8 mg/kg/day) on the following day. On day 4 after SE, video-depth EEG recordings from the hippocampal CA3 subfield and the entorhinal cortex were initiated and continued for 12 consecutive days. We found that 66.7% (12/18) of untreated animals exhibited seizures compared to 28.6% (2/7) of allopregnanolone-treated animals. Interictal spikes occurred less frequently in the CA3 subfield of allopregnanolone-treated rats (n = 4) than in untreated animals presenting (n = 4) or not presenting (n = 4) with spontaneous seizures (p < 0.05), and were less frequent in the entorhinal cortex compared to both untreated groups (p < 0.05). Finally, allopregnanolone-treated rats had significantly lower rates of interictal spikes with fast ripples (250-500 Hz) compared to untreated animals but only in CA3 (p < 0.05). Our findings show that allopregnanolone reduces the frequency of interictal spikes and fast ripples in CA3, a structure that plays an important role in ictogenesis and epileptogenesis. Neurosteroids may therefore influence pathological network activity leading to spontaneous seizures following pilocarpine-induced SE. Recordings after termination of allopregnanolone treatment will be however required to establish whether allopregnanolone exerts disease-modifying properties.
[Mh] Termos MeSH primário: Anestésicos/uso terapêutico
Ondas Encefálicas/efeitos dos fármacos
Epilepsia do Lobo Temporal/tratamento farmacológico
Pregnanolona/uso terapêutico
[Mh] Termos MeSH secundário: Anestésicos/farmacologia
Animais
Encéfalo/efeitos dos fármacos
Encéfalo/fisiopatologia
Modelos Animais de Doenças
Eletroencefalografia
Epilepsia do Lobo Temporal/induzido quimicamente
Epilepsia do Lobo Temporal/patologia
Análise de Fourier
Masculino
Agonistas Muscarínicos/toxicidade
Pilocarpina/toxicidade
Pregnanolona/farmacologia
Ratos
Ratos Sprague-Dawley
Estatísticas não Paramétricas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anesthetics); 0 (Muscarinic Agonists); 01MI4Q9DI3 (Pilocarpine); BXO86P3XXW (Pregnanolone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE


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[PMID]:28383485
[Au] Autor:Meyer A; Wree A; Günther R; Holzmann C; Schmitt O; Rolfs A; Witt M
[Ad] Endereço:Institute of Anatomy, University of Rostock, 18057 Rostock, Germany. anja.meyer@med.uni-rostock.de.
[Ti] Título:Increased Regenerative Capacity of the Olfactory Epithelium in Niemann-Pick Disease Type C1.
[So] Source:Int J Mol Sci;18(4), 2017 Apr 06.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of mutant mice compared with healthy controls ( ). Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two different therapy approaches using either a combination of miglustat, 2-hydroxypropyl-ß-cyclodextrin (HPßCD) and allopregnanolone or a monotherapy with HPßCD, we recorded a remarkable reduction of morphological damages in mice and an up to four-fold increase of proliferating cells within the olfactory epithelium. Numbers of mature olfactory receptor neurons doubled after both therapy approaches. Interestingly, we also observed therapy-induced alterations in treated controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1.
[Mh] Termos MeSH primário: Mutação
Doença de Niemann-Pick Tipo C/genética
Mucosa Olfatória/patologia
Proteínas/genética
[Mh] Termos MeSH secundário: 1-Desoxinojirimicina/administração & dosagem
1-Desoxinojirimicina/análogos & derivados
1-Desoxinojirimicina/farmacologia
2-Hidroxipropil-beta-Ciclodextrina
Animais
Apoptose/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Modelos Animais de Doenças
Seres Humanos
Camundongos
Doença de Niemann-Pick Tipo C/patologia
Mucosa Olfatória/efeitos dos fármacos
Pregnanolona/administração & dosagem
Pregnanolona/farmacologia
beta-Ciclodextrinas/administração & dosagem
beta-Ciclodextrinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Npc1 protein, mouse); 0 (Proteins); 0 (beta-Cyclodextrins); 19130-96-2 (1-Deoxynojirimycin); 1I96OHX6EK (2-Hydroxypropyl-beta-cyclodextrin); ADN3S497AZ (miglustat); BXO86P3XXW (Pregnanolone)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170407
[St] Status:MEDLINE


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[PMID]:28232221
[Au] Autor:Uppari NP; Joseph V; Bairam A
[Ad] Endereço:Centre de Recherche de l'Institut Universitaire, de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.
[Ti] Título:Respiratory responses to progesterone and allopregnanolone following chronic caffeine treatment in newborn female rats.
[So] Source:Respir Physiol Neurobiol;240:32-40, 2017 Jun.
[Is] ISSN:1878-1519
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:We recently showed that in 12-day-old male rats exposed to caffeine for 10 consecutive days, progesterone inhibits the respiratory response to hypoxia and increases apnea frequency (Uppari et al., 2016). This was partly due to a higher inhibitory response of GABAa receptor to allopregnanolone, the neuroactive metabolite of progesterone. In the present study, we addressed whether similar effects occur in females. We used newborn female rats daily gavaged with water (control) or caffeine (15mg/kg) between the postnatal (P) days 3-12. At P12, we recorded ventilation, metabolic rate, and apnea frequency and duration in normoxia and in response to moderate hypoxia, following an intraperitonial injection of progesterone (4mg/kg) or allopregnanolone (10mg/kg). In control rats, progesterone had no effect on breathing in normoxia and in hypoxia, and in rats treated with caffeine it decreased the initial increase in respiratory frequency in hypoxia. In both groups, allopregnalone decreased breathing frequency in normoxia and in hypoxia and increased the frequency of apnea in normoxia in control rats and in rats treated with caffeine. Injection of bicuculline (a specific GABAa receptor antagonist) prevented the inhibitory effects of allopregnanolone on breathing in both groups. These data indicate that chronic caffeine treatment unmasked an inhibitory effect of progesterone on the hypoxic response but this was weaker than in males, and contrasting to what was observed in male rats (Uppari et al., 2016), GABAa receptors are not significantly affected by chronic caffeine treatment in newborn female rats.
[Mh] Termos MeSH primário: Cafeína/administração & dosagem
Estimulantes do Sistema Nervoso Central/administração & dosagem
Pregnanolona/farmacologia
Progesterona/farmacologia
Respiração/efeitos dos fármacos
[Mh] Termos MeSH secundário: Análise de Variância
Anestésicos/farmacologia
Animais
Animais Recém-Nascidos
Apneia/fisiopatologia
Dióxido de Carbono/metabolismo
Combinação de Medicamentos
Feminino
Hipóxia/fisiopatologia
Masculino
Pletismografia
Progestinas/farmacologia
Ratos
Caracteres Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anesthetics); 0 (Central Nervous System Stimulants); 0 (Drug Combinations); 0 (Progestins); 142M471B3J (Carbon Dioxide); 3G6A5W338E (Caffeine); 4G7DS2Q64Y (Progesterone); BXO86P3XXW (Pregnanolone)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170426
[Lr] Data última revisão:
170426
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE



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