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https://www.readbyqxmd.com/read/29142081/genetic-and-molecular-regulation-of-extrasynaptic-gaba-a-receptors-in-the-brain-therapeutic-insights-for-epilepsy
#1
Shu-Hui Chuang, Doodipala Samba Reddy
GABA-A receptors play a pivotal role in many brain diseases. Epilepsy is caused by acquired conditions and genetic defects in GABA receptor channels regulating neuronal excitability in the brain. The latter is referred to as GABA channelopathies. In the last two decades, major advances have been made in the genetics of epilepsy. The presence of specific GABAergic genetic abnormalities leading to some of the classical epileptic syndromes has been identified. Advances in molecular cloning and recombinant systems have helped characterize mutations in GABA-A receptor subunit genes in clinical neurology...
November 15, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29079733/analgesic-effects-and-pharmacologic-mechanisms-of-the-gelsemium-alkaloid-koumine-on-a-rat-model-of-postoperative-pain
#2
Bo-Jun Xiong, Ying Xu, Gui-Lin Jin, Ming Liu, Jian Yang, Chang-Xi Yu
Postoperative pain (POP) of various durations is a common complication of surgical procedures. POP is caused by nerve damage and inflammatory responses that are difficult to treat. The neuroinflammation-glia-steroid network is known to be important in POP. It has been reported that the Gelsemium alkaloid koumine possesses analgesic, anti-inflammatory and neurosteroid modulating activities. This study was undertaken to test the analgesic effects of koumine against POP and explore the underlying pharmacologic mechanisms...
October 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29074640/tspo-mutations-in-rats-and-a-human-polymorphism-impair-the-rate-of-steroid-synthesis
#3
David R Owen, Jinjiang Fan, Enrico Campioli, Sathvika Venugopal, Andrew Midzak, Edward Daly, Aline Harlay, Leeyah Issop, Vincenzo Libri, Dimitra Kalogiannopoulou, Eduardo Oliver, Enrique Gallego-Colon, Alessandro Colasanti, Les Huson, Ilan Rabiner, Puvan Suppiah, Charles Essagian, Paul M Matthews, Vassilios Papadopoulos
The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation and apoptosis.  TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation.  In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders...
October 26, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29070563/low-serum-%C3%AF-3-and-%C3%AF-6-polyunsaturated-fatty-acids-and-other-metabolites-are-associated-with-poor-linear-growth-in-young-children-from-rural-malawi
#4
Richard D Semba, Indi Trehan, Ximin Li, Norman Salem, Ruin Moaddel, M Isabel Ordiz, Kenneth M Maleta, Klaus Kraemer, Mark J Manary
Background: Stunting affects ∼25% of children <5 y of age and is associated with impaired cognitive and motor development and increased morbidity and mortality. The pathogenesis of stunting is poorly understood.Objective: The purpose of this study was to identify altered metabolic pathways associated with child stunting.Design: We measured 677 serum metabolites using liquid chromatography-tandem mass spectrometry in a cross-sectional study of 400 Malawian children aged 12-59 mo, of whom 62% were stunted...
October 25, 2017: American Journal of Clinical Nutrition
https://www.readbyqxmd.com/read/29069423/testosterone-and-corticosterone-in-the-mesocorticolimbic-system-of-male-rats-effects-of-gonadectomy-and-caloric-restriction
#5
Daniel J Tobiansky, Anastasia M Korol, Chunqi Ma, Jordan E Hamden, Cecilia Jalabert, Ryan J Tomm, Kiran K Soma
Steroid hormones can modulate motivated behaviors through the mesocorticolimbic system. Gonadectomy (GDX) is a common method to determine how steroids influence the mesocorticolimbic system and caloric restriction (CR) is often used to invigorate motivated behaviors. The assumption is that the effect of these manipulations on brain steroid levels reflects circulating steroid levels. We now know that the brain regulates local steroid levels in a region-specific manner; however, previous studies have low spatial resolution...
October 20, 2017: Endocrinology
https://www.readbyqxmd.com/read/29066971/the-sigma-2-receptor-selective-agonist-siramesine-lu-28-179-decreases-cocaine-reinforced-pavlovian-learning-and-alters-glutamatergic-and-dopaminergic-input-to-the-striatum
#6
Anna M Klawonn, Anna Nilsson, Carl F Rådberg, Sarah H Lindström, Mia Ericson, Björn Granseth, David Engblom, Michael Fritz
Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatment-resistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29045302/neurosteroid-levels-in-patients-with-bipolar-disorder-and-a-history-of-cannabis-use-disorders
#7
Brittany L Mason, Erin Van Enkevort, Francesca Filbey, Christine E Marx, John Park, Alyson Nakamura, Prabha Sunderajan, E Sherwood Brown
PURPOSE/BACKGROUND: In animal models, levels of the neurosteroid pregnenolone increase after tetrahydrocannabinol (THC) administration and pregnenolone appears to attenuate the brain effects of THC. Given these interactions between pregnenolone and THC, we evaluated baseline neurosteroid levels in participants with a history of a cannabis use disorders (CUDs). METHODS/PROCEDURES: Bipolar depressed participants were enrolled in a randomized placebo-controlled clinical trial to evaluate the efficacy of add-on pregnenolone for depression and before receiving pregnenolone or placebo...
December 2017: Journal of Clinical Psychopharmacology
https://www.readbyqxmd.com/read/29026534/recent-advances-in-hepatic-encephalopathy
#8
REVIEW
Victoria Liere, Gurkarminder Sandhu, Sharon DeMorrow
Hepatic encephalopathy describes the array of neurological alterations that occur during acute liver failure or chronic liver injury. While key players in the pathogenesis of hepatic encephalopathy, such as increases in brain ammonia, alterations in neurosteroid levels, and neuroinflammation, have been identified, there is still a paucity in our knowledge of the precise pathogenic mechanism. This review gives a brief overview of our understanding of the pathogenesis of hepatic encephalopathy and then summarizes the significant recent advances made in clinical and basic research contributing to our understanding, diagnosis, and possible treatment of hepatic encephalopathy...
2017: F1000Research
https://www.readbyqxmd.com/read/29024742/cyp-mediated-drug-metabolism-in-the-brain-impacts-drug-response
#9
REVIEW
Douglas M McMillan, Rachel F Tyndale
The functional role of cytochrome P450 (CYP) enzymes in the brain is an exciting and evolving field of research. CYPs are present and active in the brain, with heterogeneous patterns of expression, activity, and sensitivity to modulation across cell types, regions, and species. Despite total brain CYP expression being a fraction of hepatic CYP expression, the expanding literature of in vitro and in vivo experiments have provided evidence that brain CYPs can impact acute and chronic drug response, susceptibility to damage by neurotoxins, and are associated with altered personality, behaviour, and risk of neurological disease...
October 9, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29024720/disruptions-to-the-cerebellar-gabaergic-system-in-juvenile-guinea-pigs-following-preterm-birth
#10
Julia C Shaw, Hannah K Palliser, Rebecca M Dyson, Mary J Berry, Jonathan J Hirst
BACKGROUND: Children that are born preterm are at an increased risk of developing cognitive problems and behavioural disorders, such as attention deficit hyperactivity disorder (ADHD). There is increasing interest in the role of the cerebellum in these processes and the potential involvement of GABAergic pathways in neurodevelopmental disorders. We propose that preterm birth, and the associated loss of the trophic intrauterine environment, alters the development of the cerebellum, contributing to ongoing neurobehavioral disorders...
October 9, 2017: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/28991263/structural-basis-for-gabaa-receptor-potentiation-by-neurosteroids
#11
Paul S Miller, Suzanne Scott, Simonas Masiulis, Luigi De Colibus, Els Pardon, Jan Steyaert, A Radu Aricescu
Type A γ-aminobutyric acid receptors (GABAARs) are the principal mediators of inhibitory neurotransmission in the human brain. Endogenous neurosteroids interact with GABAARs to regulate acute and chronic anxiety and are potent sedative, analgesic, anticonvulsant and anesthetic agents. Their mode of binding and mechanism of receptor potentiation, however, remain unknown. Here we report crystal structures of a chimeric GABAAR construct in apo and pregnanolone-bound states. The neurosteroid-binding site is mechanically coupled to the helices lining the ion channel pore and modulates the desensitization-gate conformation...
November 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28986464/a-role-of-endogenous-progesterone-in-stroke-cerebroprotection-revealed-by-the-neural-specific-deletion-of-its-intracellular-receptors
#12
Xiaoyan Zhu, Magalie Fréchou, Philippe Liere, Shaodong Zhang, Antoine Pianos, Fernandez Neïké, Christian Denier, Claudia Mattern, Michael Schumacher, Rachida Guennoun
Treatment with progesterone protects the male and female brain against damage after middle cerebral artery occlusion (MCAO). However, in both sexes, the brain contains significant amounts of endogenous progesterone. It is not known whether endogenously produced progesterone enhances the resistance of the brain to ischemic insult. Here, we used steroid profiling by gas chromatography-tandem mass spectrometry (GC-MS/MS) for exploring adaptive and sex-specific changes in brain levels of progesterone and its metabolites after MCAO...
October 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28969480/maternal-stress-in-pregnancy-affects-myelination-and-neurosteroid-regulatory-pathways-in-the-guinea-pig-cerebellum
#13
Greer A Bennett, Hannah K Palliser, Julia C Shaw, Kerrin L Palazzi, David W Walker, Jonathan J Hirst
Prenatal stress predisposes offspring to behavioral pathologies. These may be attributed to effects on cerebellar neurosteroids and GABAergic inhibitory signaling, which can be linked to hyperactivity disorders. The aims were to determine the effect of prenatal stress on markers of cerebellar development, a key enzyme in neurosteroid synthesis and the expression of GABAA receptor (GABAAR) subunits involved in neurosteroid signaling. We used a model of prenatal stress (strobe light exposure, 2 h on gestational day 50, 55, 60 and 65) in guinea pigs, in which we have characterized anxiety and neophobic behavioral outcomes...
October 2, 2017: Stress: the International Journal on the Biology of Stress
https://www.readbyqxmd.com/read/28967882/crystal-structures-of-a-gabaa-receptor-chimera-reveal-new-endogenous-neurosteroid-binding-sites
#14
Duncan Laverty, Philip Thomas, Martin Field, Ole J Andersen, Matthew G Gold, Philip C Biggin, Marc Gielen, Trevor G Smart
γ-Aminobutyric acid receptors (GABAARs) are vital for controlling excitability in the brain. This is emphasized by the numerous neuropsychiatric disorders that result from receptor dysfunction. A critical component of most native GABAARs is the α subunit. Its transmembrane domain is the target for many modulators, including endogenous brain neurosteroids that impact anxiety, stress and depression, and for therapeutic drugs, such as general anesthetics. Understanding the basis for the modulation of GABAAR function requires high-resolution structures...
November 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28951257/protective-effects-of-the-neurosteroid-allopregnanolone-in-a-mouse-model-of-spontaneous-motoneuron-degeneration
#15
Maria Meyer, Laura I Garay, María Sol Kruse, Agustina Lara, Gisella Gargiulo-Monachelli, Michael Schumacher, Rachida Guennoun, Hector Coirini, Alejandro F De Nicola, Maria Claudia Gonzalez Deniselle
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...
November 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28950923/adverse-life-events-psychiatric-history-and-biological-predictors-of-postpartum-depression-in-an-ethnically-diverse-sample-of-postpartum-women
#16
J Guintivano, P F Sullivan, A M Stuebe, T Penders, J Thorp, D R Rubinow, S Meltzer-Brody
BACKGROUND: Race, psychiatric history, and adverse life events have all been independently associated with postpartum depression (PPD). However, the role these play together in Black and Latina women remains inadequately studied. Therefore, we performed a case-control study of PPD, including comprehensive assessments of symptoms and biomarkers, while examining the effects of genetic ancestry. METHODS: We recruited our sample (549 cases, 968 controls) at 6 weeks postpartum from obstetrical clinics in North Carolina...
September 27, 2017: Psychological Medicine
https://www.readbyqxmd.com/read/28948817/vitamin-d-neurosteroids-and-autism
#17
L Máčová, M Bičíková, D Ostatníková, M Hill, L Stárka
Vitamin D had been for a long time investigated for its effects on bone metabolism. Recently has been observed that the incidence of some neurodevelopmental disorders (including autism) increases hand in hand with vitamin D deficiency. Indeed, vitamin D was reported to modulate the biosynthesis of neurotransmitters and neurotrophic factors; moreover, its receptor was found in the central nervous system. Vitamin D deficiency was therefore assessed as a risk factor for autism, however the biological mechanism has not yet been revealed...
September 26, 2017: Physiological Research
https://www.readbyqxmd.com/read/28947342/apigenin-inhibits-rat-neurosteroidogenic-5%C3%AE-reductase-1-and-3%C3%AE-hydroxysteroid-dehydrogenase
#18
Ying Wu, Lili Li, Songyi Zhou, Qiuxia Shen, Han Lin, Qiqi Zhu, Jianliang Sun, Ren-Shan Ge
Apigenin, a common flavonoid, has extensive pharmacological activities. Apigenin inhibits some steroid biosynthetic enzymes, suggesting that it may block neurosteroid synthesis. Neurosteroids play many important roles in neurological functions. The objective of the present study is to investigate effects of apigenin on neurosteroidogenic enzymes, 5α-reductase 1 (SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C9), and retinol dehydrogenase 2 (RoDH2), in rats. SRD5A1, AKR1C9, and RoDH2 were expressed in COS-1 cells and the effects of apigenin on these enzymes and modes of action were explored using radiolabeled substrates and thin-layer chromatographic separation coupled with radiometry...
September 22, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28947177/resveratrol-ameliorated-the-behavioral-deficits-in-a-mouse-model-of-post-traumatic-stress-disorder
#19
Ze-Shun Zhang, Zhi-Kun Qiu, Jia-Li He, Xu Liu, Ji-Sheng Chen, Yu-Lu Wang
Post-traumatic stress disorder (PTSD) has become a major psychiatric and neurological issue. Resveratrol is shown to be effective on depression and anxiety. However, the mechanism of anti-PTSD-like effects of resveratrol remains unknown. The present study aimed to explore the possible molecular and cellular mechanisms underlying the anti-PTSD-like effects of resveratrol. Following a 2-day exposure to inescapable electric foot shocks, animals were administered resveratrol (10, 20, and 40mg/kg, i.g.) during the behavioral tests, which included contextual freezing measurement, elevated plus maze test, staircase test, and open field test...
October 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28942480/acute-inhibition-of-estradiol-synthesis-impacts-vestibulo-ocular-reflex-adaptation-and-cerebellar-long-term-potentiation-in-male-rats
#20
Cristina V Dieni, Aldo Ferraresi, Jacqueline A Sullivan, Sivarosa Grassi, Vito E Pettorossi, Roberto Panichi
The vestibulo-ocular reflex (VOR) adaptation is an ideal model for investigating how the neurosteroid 17 beta-estradiol (E2) contributes to the modification of behavior by regulating synaptic activities. We hypothesized that E2 impacts VOR adaptation by affecting cerebellar synaptic plasticity at the parallel fiber-Purkinje cell (PF) synapse. To verify this hypothesis, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in adaptation of the VOR in male rats using an oral dose (2...
September 23, 2017: Brain Structure & Function
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