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Shimriet Zeidler, Andreea S Pop, Israa A Jaafar, Helen de Boer, Ronald A M Buijsen, Celine E F de Esch, Ingeborg Nieuwenhuizen-Bakker, Renate K Hukema, Rob Willemsen
INTRODUCTION: Fragile X syndrome (FXS) is a common monogenetic cause of intellectual disability, autism spectrum features, and a broad range of other psychiatric and medical problems. FXS is caused by the lack of the fragile X mental retardation protein (FMRP), a translational regulator of specific mRNAs at the postsynaptic compartment. The absence of FMRP leads to aberrant synaptic plasticity, which is believed to be caused by an imbalance in excitatory and inhibitory network functioning of the synapse...
April 26, 2018: Brain and Behavior
Jiajia Ma, Jiahui Lin, Lifang Zhao, Klaus Harms, Michael Marsch, Xiulan Xie, Eric Meggers
Beta-Substituted chiral gamma-aminobutyric acids display important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein we report an efficient catalytic enantioselective approach for the synthesis of beta-substituted gamma-aminobutyric acid derivatives through visible-light-induced photocatalyst-free asymmetric radical conjugate additions. Various beta-substituted gamma-aminobutyric acid analogs, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (53-89%) and with excellent enantioselectivities (90-97% ee)...
April 30, 2018: Angewandte Chemie
Xiuxiu Li, Cai You, Yusheng Yang, Yuhong Yang, Pan Li, Guoxian Gu, Lung Wa Chung, Hui Lv, Xumu Zhang
With the assistance of hydrogen bonds, the first asymmetric hydrogenation of β-cyanocinnamic esters is developed, affording chiral β-cyano esters with excellent enantioselectivities (up to 99% ee). This novel methodology provides an efficient and concise synthetic route to chiral GABA-derivatives such as ( S )-Pregabalin, ( R )-Phenibut, ( R )-Baclofen. Interestingly, in this system, the catalyst with a single H-bond donor performs better than that with double H-bond donors, which is a novel discovery in the metalorganocatalysis area...
February 21, 2018: Chemical Science
Laura J Stoppel, Tatiana M Kazdoba, Melanie D Schaffler, Anthony R Preza, Arnold Heynen, Jacqueline N Crawley, Mark F Bear
Human chromosome 16p11.2 microdeletion is among the most common gene copy number variations (CNVs) known to confer risk for intellectual disability (ID) and autism spectrum disorder (ASD) and affects an estimated 3 in 10 000 people. Caused by a single copy deletion of ~27 genes, 16p11.2 microdeletion syndrome is characterized by ID, impaired language, communication and socialization skills, and ASD. Studies in animal models where a single copy of the syntenic 16p11.2 region has been deleted have revealed morphological, behavioral, and electrophysiological abnormalities...
February 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
R Michelle Saré, Lee Harkless, Merlin Levine, Anita Torossian, Carrie A Sheeler, Carolyn B Smith
In patients with fragile X syndrome (FXS), sleep problems are commonly observed but are not well characterized. In animal models of FXS (dfmr1 and Fmr1 knockout (KO)/Fxr2 heterozygote) circadian rhythmicity is affected, but sleep per se has not been examined. We used a home-cage monitoring system to assess total sleep time in both light and dark phases in Fmr1 KO mice at different developmental stages. Fmr1 KOs at P21 do not differ from controls, but genotype × phase interactions in both adult (P70 and P180) groups are statistically significant indicating that sleep in Fmr1 KOs is reduced selectively in the light phase compared to controls...
2017: Frontiers in Molecular Neuroscience
Mousa Hamad, Ryan Holland, Naveed Kamal, Robert Luceri, Antonios Mammis
INTRODUCTION: Essential tremor (ET) is the most common movement disorder of adults, affecting an estimated 7 million Americans. Symptoms of ET range from slightly noticeable to debilitating, with 1 cohort study finding 15% of patients were forced into early retirement. Additionally, depression has also been correlated with the severity of disability of ET. Treatment options include propranolol and primidone. Current treatment options are not very effective, with more than half (56.3%) of patients discontinuing medications because of no changes in symptoms...
September 2017: World Neurosurgery
Ji-Yong Kang, Jayashree Chadchankar, Thuy N Vien, Michelle I Mighdoll, Thomas M Hyde, Robert J Mather, Tarek Z Deeb, Menelas N Pangalos, Nicholas J Brandon, John Dunlop, Stephen J Moss
The behavioral and anatomical deficits seen in fragile X syndrome (FXS) are widely believed to result from imbalances in the relative strengths of excitatory and inhibitory neurotransmission. Although modified neuronal excitability is thought to be of significance, the contribution that alterations in GABAergic inhibition play in the pathophysiology of FXS are ill defined. Slow sustained neuronal inhibition is mediated by γ-aminobutyric acid type B (GABAB ) receptors, which are heterodimeric G-protein-coupled receptors constructed from R1a and R2 or R1b and R2 subunits...
April 21, 2017: Journal of Biological Chemistry
C R Kasten, A M Frazee, S L Boehm
Although United States smoking rates have been on the decline over the past few decades, cigarette smoking still poses a critical health and economic threat. Very few treatment options for smoking exist, and many of them do not lead to long-term abstinence. Preclinical models are necessary for understanding the effects of nicotine and developing treatments. Current self-administration models of nicotine intake may require surgical procedures and often result in low levels of intake. Further, they do not lend themselves to investigating treatments...
September 2016: Pharmacology, Biochemistry, and Behavior
Irene Lorrai, Paola Maccioni, Gian Luigi Gessa, Giancarlo Colombo
Racemic baclofen [(±)-baclofen] has repeatedly been reported to suppress several -alcohol-motivated behaviors, including alcohol drinking and alcohol -self-administration, in rats and mice. Recent data suggested that baclofen may have bidirectional, stereospecific effects, with the more active enantiomer, R(+)-baclofen, suppressing alcohol intake and the less active enantiomer, S(-)-baclofen, stimulating alcohol intake in mice. The present study was designed to investigate whether this enantioselectivity of baclofen effects may also extend to the reinforcing properties of alcohol in rats...
2016: Frontiers in Psychiatry
Yujiro Hayashi, Daisuke Sakamoto, Daichi Okamura
An efficient asymmetric total synthesis of (S)-baclofen was accomplished via a one-pot operation from commercially available materials using sequential reactions, such as aldol condensation of acetaldehyde, diphenylprolinol silyl ether mediated asymmetric Michael reaction of nitromethane, Kraus-Pinnick oxidation, and Raney Ni reduction. Highly enantioenriched baclofen was obtained in one pot with a good yield over four reactions.
January 4, 2016: Organic Letters
Tsuyoshi Mita, Yuki Higuchi, Yoshihiro Sato
Various allylic alcohols were carboxylated in the presence of a catalytic amount of PdCl2 and PPh3 using ZnEt2 as a stoichiometric transmetalation agent under a CO2 atmosphere (1 atm). This carboxylation proceeded in a highly regioselective manner to afford branched carboxylic acids predominantly. The β,γ-unsaturated carboxylic acid thus obtained was successfully converted into an optically active γ-butyrolactone, a known intermediate of (R)-baclofen.
November 9, 2015: Chemistry: a European Journal
Deborah S Raithel, Kirsten H Ohler, Isabel Porto, Alma R Bicknese, Donna M Kraus
Paroxysmal sympathetic hyperactivity (PSH) is a life-threatening condition characterized by hyperadrenergic activity and autonomic dysfunction. Also termed autonomic storms, PSH can occur after a variety of cerebral insults, most commonly traumatic brain injury. Limited pediatric literature is available, especially in patients with brain injury from hypoxia. No consensus exists for the terminology, diagnostic criteria, or treatment algorithm for PSH. Thus, the optimal management, including medication selection and dosing, remains unclear...
July 2015: Journal of Pediatric Pharmacology and Therapeutics: JPPT: the Official Journal of PPAG
I V Belozertseva, O A Dravolina, M A Tur, S R Kuvarzin, E E Zvartau
AIM: To adopt and validate the Straub tail reaction (SR) for comparative assessment of spastic effects of serotonergic compounds. MATERIAL AND METHODS: To measure the muscle relaxant activity, the morphine-induced Straub-tail assay was used. SR was graded according to modified intensity-score basis in a scale decribed by Kameyama et al. (1978). Subcutaneous injections of different doses of morphine (10-60 mg/kg) induced a dose-dependent SR with maximum response obtained 15-30 min after the morphine administration...
2015: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Gregory B Bissonette, Matthew R Roesch
Cognitive flexibility is a hallmark of prefrontal cortical (PFC) function yet little is known about downstream area involvement. The medial dorsal striatum (mDS) receives major projections from the PFC and is uniquely situated to perform the integration of responses with rule information. In this study, we use a novel rule shifting task in rats that mirrors non-human primate and human studies in its temporal precision and counterbalanced responses. We record activity from single neurons in the mDS while rats switch between different rules for reward...
October 2015: European Journal of Neuroscience
Elliott Kyung Lee, Alan Bruce Douglass
Narcolepsy is a disabling sleep disorder characterized by daytime hypersomnolence. Those with cataplexy have spells of muscle weakness precipitated by strong emotions, especially laughter or surprise. Cataplexy treatments include antidepressants or a GABA-B agonist, gamma hydroxybutyrate (GHB). GHB is the most effective treatment for cataplexy, but is expensive and can have significant side effects. A recent report of a murine model of narcolepsy-cataplexy suggests R-baclofen has potential efficacy against cataplexy...
2015: Nature and Science of Sleep
Liga Zvejniece, Edijs Vavers, Baiba Svalbe, Grigory Veinberg, Kristina Rizhanova, Vilnis Liepins, Ivars Kalvinsh, Maija Dambrova
Phenibut is clinically used anxiolytic, mood elevator and nootropic drug. R-phenibut is responsible for the pharmacological activity of racemic phenibut, and this activity correlates with its binding affinity for GABAB receptors. In contrast, S-phenibut does not bind to GABAB receptors. In this study, we assessed the binding affinities of R-phenibut, S-phenibut, baclofen and gabapentin (GBP) for the α2-δ subunit of the voltage-dependent calcium channel (VDCC) using a subunit-selective ligand, radiolabelled GBP...
October 2015: Pharmacology, Biochemistry, and Behavior
Jing Wang, Deb Kumar Mojumder, Jun Yan, An Xie, Robert F Standaert, Haohua Qian, David R Pepperberg, Laura J Frishman
All three classes of receptors for the inhibitory neurotransmitter GABA (GABAR) are expressed in the retina. This study investigated roles of GABAR, especially GABACR (GABA(A)-ρ), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABACR versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABACR(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABACR antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABAAR antagonist, SR95531; GABABR antagonist, CGP, and agonist, baclofen...
October 2015: Experimental Eye Research
Amer Dastgir, Nathan J Ranalli, Theresa L MacGregor, Philipp R Aldana
The authors report an unusual case of intrathecal baclofen withdrawal due to the perforation and subsequent leakage of a baclofen pump catheter in a patient with spastic cerebral palsy. A 15-year-old boy underwent an uncomplicated placement of an intrathecal baclofen pump for the treatment of spasticity due to cerebral palsy. After excellent control of symptoms for 3 years, the patient presented to the emergency department with increasing tremors following a refill of his baclofen pump. Initial evaluation consisted of radiographs of the pump and catheter, which appeared normal, and a successful aspiration of CSF from the pump's side port...
September 2015: Journal of Neurosurgery. Pediatrics
Kristen R Nichols, Chad A Knoderer, Nicholas G Jackson, John J Manaloor, John C Christenson
A 13-year-old female experienced a recurrence of baclofen pump-related central nervous system (CNS) infection caused by Achromobacter, despite absence of retained foreign material. Due to the failure of meropenem (120 mg/kg/d in divided doses every 8 hours and infused over 30 minutes) in the initial infection, the dose was infused over 4 hours during the recurrence. Meropenem is an antibiotic for which efficacy is time dependent, and 4-hour versus 30-minute infusions have been shown to prolong the time the concentration of the antibiotic exceeds the minimum inhibitory concentration (MIC) of the organism at the site of infection (T>MIC)...
August 2015: Journal of Pharmacy Practice
Monica Blichowski, Alexander Shephard, Jessica Armstrong, Liqing Shen, Miguel A Cortez, James H Eubanks, O Carter Snead
OBJECTIVE: Infantile spasms (or IS) is a catastrophic childhood epilepsy that is particularly prevalent in children with Down syndrome. Previously, we have shown that the Ts65Dn (Ts) mouse model of Down syndrome is a useful substrate upon which to develop an animal model of infantile spasms. Specifically, the Ts mouse is exquisitely sensitive to the electroencephalography (EEG) and behavioral effects of γ-aminobutyric acid (GABA) B receptor (GABA(B)R) agonists with a resultant phenotype that bears behavioral, EEG, and pharmacologic semblance to infantile spasms in humans...
July 2015: Epilepsia
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