Short-term treatment with the GABAA receptor antagonist pentylenetetrazole produces a sustained pro-cognitive benefit in a mouse model of Down's syndrome.

Abstract:

BACKGROUND AND PURPOSE:Down's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normalized by low doses of GABAA receptor antagonists in adult animals. In this study, we explore the therapeutic potential of pentylenetetrazole, a GABAA receptor antagonist with a history of safe use in humans. EXPERIMENTAL APPROACH:Long-term memory was assessed by the novel object recognition test in different cohorts of TS mice after a delay following a short-term chronic treatment with pentylenetetrazole. Seizure susceptibility, an index of treatment safety, was studied by means of EEG, behaviour and hippocampus morphology. EEG spectral analysis was used as a bio-marker of the treatment. KEY RESULTS:PTZ has a wide therapeutic window (0.03-3 mg·kg(-1)) that is >10-1000-fold below its seizure threshold and chronic pentylenetetrazole treatment did not lower the seizure threshold. Short-term, low, chronic dose regimens of pentylenetetrazole elicited long-lasting (>1 week) normalization of cognitive function in young and aged mice. Pentylenetetrazole effectiveness was dependent on the time of treatment; cognitive performance improved after treatment during the light (inactive) phase, but not during the dark (active) phase. Chronic pentylenetetrazole treatment normalized EEG power spectra in TS mice. CONCLUSIONS AND IMPLICATIONS:Low doses of pentylenetetrazole were safe, produced long-lasting cognitive improvements and have the potential of fulfilling an unmet therapeutic need in Down's syndrome.

journal_name

Br J Pharmacol

authors

Colas D,Chuluun B,Warrier D,Blank M,Wetmore DZ,Buckmaster P,Garner CC,Heller HC

doi

10.1111/bph.12169

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

963-73

issue

5

eissn

0007-1188

issn

1476-5381

journal_volume

169

pub_type

杂志文章
  • Anticonvulsant effect of BmK IT2, a sodium channel-specific neurotoxin, in rat models of epilepsy.

    abstract:BACKGROUND AND PURPOSE:The sodium channel is a primary target for treating central nervous system disorders such as epilepsy. In this study the anticonvulsant effect of BmK IT2, a sodium channel-specific neurotoxin, was evaluated in different animal models of epilepsy. EXPERIMENTAL APPROACH:Experiments were performed ...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1038/bjp.2008.156

    authors: Zhao R,Zhang XY,Yang J,Weng CC,Jiang LL,Zhang JW,Shu XQ,Ji YH

    更新日期:2008-07-01 00:00:00

  • The beta 1- and beta 2-adrenoceptor stimulatory effects of alprenolol, oxprenolol and pindolol: a study in the isolated right atrium and uterus of the rat.

    abstract::The rat isolated right atrium (frequency response) and progesterone-treated rat uterus (relaxation) were used to examine the beta 1- and beta 2-adrenoceptor stimulatory effects of alprenolol, oxprenolol and pindolol. In addition, the beta 1-adrenoceptor stimulatory effect of practolol was studied in the right atrium. ...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1986.tb14582.x

    authors: Abrahamsson T

    更新日期:1986-04-01 00:00:00

  • Potent and voltage-dependent block by philanthotoxin-343 of neuronal nicotinic receptor/channels in PC12 cells.

    abstract::1. Block by philanthotoxin-343 (PhTX-343), a neurotoxin from wasps, of ionic currents mediated through neuronal nicotinic acetylcholine (ACh) receptor/channels was characterized in rat phaeochromocytoma PC12 cells, by use of whole cell voltage-clamp techniques. 2. In the cells held at -60 mV, PhTX-343 at 0.1 and 1 mic...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1038/sj.bjp.0701373

    authors: Liu M,Nakazawa K,Inoue K,Ohno Y

    更新日期:1997-09-01 00:00:00

  • A model for receptor-peptide binding at the glucagon-like peptide-1 (GLP-1) receptor through the analysis of truncated ligands and receptors.

    abstract::1. The receptor for glucagon-like peptide-1 (GLP-1) can be activated by both its physiological hormone and a peptide discovered in the venom of the Gila Monster, exendin-4, which shows promise as an antidiabetic agent. 2. Exendin-4 displays receptor-binding properties not observed for GLP-1. Firstly, exendin-4 can be ...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1038/sj.bjp.0705453

    authors: Al-Sabah S,Donnelly D

    更新日期:2003-09-01 00:00:00

  • Intracellular machinery for the transport of AMPA receptors.

    abstract::AMPA-type glutamate receptors are one of the most dynamic components of excitatory synapses. Their regulated addition and removal from synapses leads to long-lasting forms of synaptic plasticity, known as long-term potentiation (LTP) and long-term depression (LTD). In addition, AMPA receptors reach their synaptic targ...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章,评审

    doi:10.1038/sj.bjp.0707525

    authors: Esteban JA

    更新日期:2008-03-01 00:00:00

  • The central and regional cardiovascular responses to intravenous and intracoronary administration of the phenyldihydropyridine elgodipine in anaesthetized pigs.

    abstract::1. The central and regional cardiovascular responses to intravenous (0.3, 1.0, 3.0 and 10.0 micrograms kg-1 min-1) and intracoronary (0.3, 0.9, 3.0 and 4.5 micrograms kg-1 min-1) infusions of elgodipine, a phenyldihydropyridine, and its solvent were studied in anaesthetized pigs. 2. Elgodipine (i.v.) caused dose-depen...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1990.tb14708.x

    authors: Sassen LM,Soei LK,Koning MM,Verdouw PD

    更新日期:1990-02-01 00:00:00

  • Relaxation of cat trachea by beta-adrenoceptor agonists can be mediated by both beta1- and beta2-adrenoceptors and potentiated by inhibitors of extraneuronal uptake.

    abstract::1--Responses (relaxation) to the beta-adrenoceptor agonists, isoprenaline, fenoterol or noradrenaline, were obtained on cat tracheal preparations contracted with a submaximal concentration of carbachol (0.5 microM). 2--The relative potencies of isoprenaline: fenoterol: noradrenaline were 100:8.1:10.7. From this, it wa...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1983.tb09406.x

    authors: O'Donnell SR,Wanstall JC

    更新日期:1983-02-01 00:00:00

  • ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis.

    abstract::Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) ...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章,评审

    doi:10.1111/bph.12159

    authors: Simões e Silva AC,Silveira KD,Ferreira AJ,Teixeira MM

    更新日期:2013-06-01 00:00:00

  • Metabolism of isoprenaline after aerosol and direct intrabronchial administration in man and dog.

    abstract::1 Administration of isoprenaline by aerosol inhalation to man results in over 80% being metabolized to the sulphate conjugate.2 The majority of an inhaled dose is probably swallowed since the metabolic pattern resembles that after an oral dose.3 Isoprenaline, administered in aqueous solution directly into the bronchia...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1974.tb08593.x

    authors: Blackwell EW,Briant RH,Conolly ME,Davies DS,Dollery CT

    更新日期:1974-04-01 00:00:00

  • What skeletal muscle has to say in amyotrophic lateral sclerosis: Implications for therapy.

    abstract::Amyotrophic lateral sclerosis (ALS) is an adult onset disorder characterized by progressive neuromuscular junction (NMJ) dismantling and degeneration of motor neurons leading to atrophy and paralysis of voluntary muscles responsible for motion and breathing. Except for a minority of patients harbouring genetic mutatio...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章,评审

    doi:10.1111/bph.15276

    authors: Manzano R,Toivonen JM,Moreno-Martínez L,de la Torre M,Moreno-García L,López-Royo T,Molina N,Zaragoza P,Calvo AC,Osta R

    更新日期:2020-09-28 00:00:00

  • The interaction of trazodone with rat brain muscarinic cholinoceptors.

    abstract::The muscarinic receptor binding of trazodone, a new nontricyclic antidepressant, was compared with established tricyclic antidepressants. The ability to inhibit the binding of [3H]-quinuclidinyl benzilate in vitro was used for comparing atropine-like effects. Trazodone was found to have essentially no activity at the ...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1980.tb10947.x

    authors: Hyslop DK,Taylor DP

    更新日期:1980-01-01 00:00:00

  • Identification of a potent and highly efficacious, yet slowly desensitizing CB1 cannabinoid receptor agonist.

    abstract::1 The relationship of agonist efficacy to the rate of G protein-coupled receptor signaling desensitization is controversial. 2 Expressing inwardly rectifying potassium channels (GIRKs) in Xenopus oocytes, we have devised a signaling assay that clearly identifies CB1 cannabinoid receptor agonists with low intrinsic eff...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1038/sj.bjp.0705792

    authors: Luk T,Jin W,Zvonok A,Lu D,Lin XZ,Chavkin C,Makriyannis A,Mackie K

    更新日期:2004-06-01 00:00:00

  • The rabbit motilin receptor: molecular characterisation and pharmacology.

    abstract::Following identification of the human motilin receptor, we isolated the rabbit orthologue by PCR amplification and found this to be 85% identical to the open reading frame of the human receptor. The protein encoded was 84% identical to the human polypeptide. In HEK293T cells transfected with the rabbit receptor, motil...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1038/sj.bjp.0705505

    authors: Dass NB,Hill J,Muir A,Testa T,Wise A,Sanger GJ

    更新日期:2003-11-01 00:00:00

  • Trigeminal antidromic vasodilatation and plasma extravasation in the rat: effects of acetylcholine antagonists and cholinesterase inhibitors.

    abstract::Antidromic stimulation of sensory peripheral branches of the trigeminal system (mental nerve) leads to cutaneous vasodilatation and increases vascular permeability in the rat. Antidromic vasodilatation is observed only at high intensity stimulation (10 V, 15 Hz, 0.2 or 5 ms) supporting the participation of afferent C-...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1985.tb16144.x

    authors: Couture R,Cuello AC,Henry JL

    更新日期:1985-03-01 00:00:00

  • The mechanism for the contraction induced by leukotriene C4 in guinea-pig taenia coli.

    abstract::The mechanism underlying the LTC(4)-induced contraction of guinea-pig taenia coli was determined using the simultaneous measurements of [Ca(2+)](i) and force in whole muscle preparations. Additional experiments were performed in receptor coupled permeabilized preparation. For comparison purposes, the contraction which...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1038/sj.bjp.0704122

    authors: Ieiri S,Nishimura J,Hirano K,Suita S,Kanaide H

    更新日期:2001-06-01 00:00:00

  • The role of alpha2-adrenoceptor antagonism in the anti-cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat.

    abstract::1. The mechanism underlying the anticataleptic properties of the atypical neuroleptic agent, clozapine, has been investigated in the rat. 2.The close structural analogues of clozapine, loxapine (0.1 mg kg(-1) s.c.) and iso-clozapine (1 and 3 mg kg(-1) s.c.) induced catalepsy in rats. In contrast, clozapine and the reg...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1038/sj.bjp.0701975

    authors: Kalkman HO,Neumann V,Hoyer D,Tricklebank MD

    更新日期:1998-08-01 00:00:00

  • Evidence that the accumulation of 5-hydroxytryptamine in the liver but not in the brain may cause the hypoglycaemia induced by 5-hydroxytryptophan.

    abstract::Experiments were undertaken to determine whether the site of the hypoglycaemic action of 5-hydroxytryptophan (5-HTP), a direct precursor of 5-hydroxytryptamine (5-HT), was in the central nervous system or in the liver. The fall in blood glucose followed the rapid increase in the amount of 5-HT both in the brain and li...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1985.tb10553.x

    authors: Endo Y

    更新日期:1985-07-01 00:00:00

  • TNF-alpha, inefficient by itself, potentiates IL-1beta-induced PGHS-2 expression in human pulmonary microvascular endothelial cells: requirement of NF-kappaB and p38 MAPK pathways.

    abstract::1: Prostaglandin H synthase-2 (PGHS-2), is an inducible enzyme involved in various inflammatory responses. We established here that interleukin-1beta (IL-1beta) but not tumour necrosis factor-alpha (TNF-alpha) increased its expression in human pulmonary microvascular endothelial cells (HPMEC). However, associated with...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1038/sj.bjp.0704811

    authors: Said FA,Werts C,Elalamy I,Couetil JP,Jacquemin C,Hatmi M

    更新日期:2002-08-01 00:00:00

  • Effects of cocaine or denervation on responses of isolated strips of cat spleen to (-)-noradrenaline and (-)-isoprenaline.

    abstract::1. A study has been made of the effects of cocaine and sympathetic denervation on responses of the cat spleen to (-)-noradrenaline and (-)-isoprenaline.2. Responses of isolated strips of spleen capsule to (-)-noradrenaline or to (-)-isoprenaline were not affected by reserpine-pretreatment.3. In adult cats, cocaine (1 ...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1973.tb08255.x

    authors: Granata AR,Langer SZ

    更新日期:1973-08-01 00:00:00

  • The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels.

    abstract:BACKGROUND AND PURPOSE:Palmitoylethanolamide (PEA) is an endogenous congener of anandamide and potentiates its actions at cannabinoid CB1 and CB2 receptors, and at transient receptor potential vanilloid type-1 (TRPV1) channels. The other endocannabinoid, 2-arachidonoylglycerol (2-AG), was recently suggested to act as a...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/bph.13084

    authors: Petrosino S,Schiano Moriello A,Cerrato S,Fusco M,Puigdemont A,De Petrocellis L,Di Marzo V

    更新日期:2016-04-01 00:00:00

  • Evidence that nitric oxide is an endogenous antiangiogenic mediator.

    abstract::1. The involvement of nitric oxide (NO) in the regulation of angiogenesis was examined in the in vivo system of the chorioallantoic membrane (CAM) of the chick embryo and in the matrigel tube formation assay. 2. Sodium nitroprusside (SNP) (0.37-28 nmol/disc), which releases NO spontaneously, caused a dose-dependent in...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1994.tb14822.x

    authors: Pipili-Synetos E,Sakkoula E,Haralabopoulos G,Andriopoulou P,Peristeris P,Maragoudakis ME

    更新日期:1994-03-01 00:00:00

  • Characterization of the prostanoid receptor profile of enprostil and isomers in smooth muscle and platelets in vitro.

    abstract::1. Enprostil is composed, in approximately equal proportions, of 4 allenic isomers which are prostanoids structurally related to prostaglandin E2 (PGE2). The isomers are denoted as RS-86505-007, RS-86812-007 which are in the 'natural' R and S configuration (with respect to PGE2) and RS-86505-008 and RS-86812-008 which...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1989.tb12682.x

    authors: Eglen RM,Whiting RL

    更新日期:1989-12-01 00:00:00

  • Effects of endorphins on different parts of the gastrointestinal tract of rat and guinea-pig in vitro.

    abstract::1 The spasmogenic and spasmolytic effects of beta-lipotropin (LPH) fragments and one analogue were investigated on different parts of the gastro-intestinal tract of guinea-pig and rat in vitro.2 Changes in muscle tone were observed in colon and rectum and to a lesser extent in jejunum and ileum of both species. Rat co...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.1980.tb10849.x

    authors: Nijkamp FP,Van Ree JM

    更新日期:1980-04-01 00:00:00

  • No proarrhythmic properties of the antibiotics Moxifloxacin or Azithromycin in anaesthetized dogs with chronic-AV block.

    abstract:BACKGROUND & PURPOSE:The therapeutically available quinolone antibiotic moxifloxacin has been used as a positive control for prolonging the QT interval in both clinical and non-clinical studies designed to assess the potential of new drugs to delay cardiac repolarization. Despite moxifloxacin prolonging QT, it has not ...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1038/sj.bjp.0706900

    authors: Thomsen MB,Beekman JD,Attevelt NJ,Takahara A,Sugiyama A,Chiba K,Vos MA

    更新日期:2006-12-01 00:00:00

  • Effects of β-adrenoceptor stimulation on delayed rectifier K(+) currents in canine ventricular cardiomyocytes.

    abstract:BACKGROUND AND PURPOSE:While the slow delayed rectifier K(+) current (I(Ks)) is known to be enhanced by the stimulation of β-adrenoceptors in several mammalian species, phosphorylation-dependent regulation of the rapid delayed rectifier K(+) current (I(Kr)) is controversial. EXPERIMENTAL APPROACH:In the present study,...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.2010.01092.x

    authors: Harmati G,Bányász T,Bárándi L,Szentandrássy N,Horváth B,Szabó G,Szentmiklósi JA,Szénási G,Nánási PP,Magyar J

    更新日期:2011-02-01 00:00:00

  • Spasticity therapy reacts to astrocyte GluA1 receptor upregulation following spinal cord injury.

    abstract::For almost three decades intrathecal baclofen therapy has been the standard treatment for spinal cord injury spasticity when oral medication is ineffective or produces serious side effects. Although intrathecal baclofen therapy has a good clinical benefit-risk ratio for spinal spasticity, tolerance and the life-threat...

    journal_title:British journal of pharmacology

    pub_type: 评论,杂志文章

    doi:10.1111/j.1476-5381.2010.00964.x

    authors: Gómez-Soriano J,Goiriena E,Taylor J

    更新日期:2010-11-01 00:00:00

  • Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats.

    abstract:BACKGROUND AND PURPOSE:mTOR inhibitors are currently used as immunosuppressants in transplanted patients and as promising anti-cancer agents. However, new-onset diabetes is a frequent complication occurring in patients treated with mTOR inhibitors such as rapamycin (Sirolimus). Here, we investigated the mechanisms asso...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1476-5381.2011.01716.x

    authors: Deblon N,Bourgoin L,Veyrat-Durebex C,Peyrou M,Vinciguerra M,Caillon A,Maeder C,Fournier M,Montet X,Rohner-Jeanrenaud F,Foti M

    更新日期:2012-04-01 00:00:00

  • Neuroadaptations of presynaptic and postsynaptic GABAB receptor function in the paraventricular nucleus in response to chronic unpredictable stress.

    abstract:BACKGROUND AND PURPOSE:Chronic stress impairs GABAA (GABA type A) receptor-mediated inhibition in the hypothalamic paraventricular nucleus (PVN). It is not clear whether GABAB receptor function is also altered. We hypothesize that chronic stress alters GABAB receptor function in PVN corticotrophin-releasing hormone (CR...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章

    doi:10.1111/bph.13924

    authors: Gao Y,Zhou JJ,Zhu Y,Wang L,Kosten TA,Zhang X,Li DP

    更新日期:2017-09-01 00:00:00

  • Targeting TDP-43 proteinopathy with drugs and drug-like small molecules.

    abstract::Following the discovery of the involvement of the ribonucleoprotein TDP-43 in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), a major research focus has been to develop treatments that can prevent or alleviate these disease conditions. One pharmacological approach has been to use TDP-...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章,评审

    doi:10.1111/bph.15148

    authors: Buratti E

    更新日期:2020-05-29 00:00:00

  • Molecular pharmacology of G protein-coupled receptors. Editorial.

    abstract::G protein-coupled receptors are the largest group of membrane proteins and are the targets for approximately 30% of drugs currently used therapeutically. These 7-transmembrane-spanning proteins continue to provide new opportunities to develop therapeutics based on emerging knowledge of their structure, signalling prop...

    journal_title:British journal of pharmacology

    pub_type: 社论

    doi:10.1111/j.1476-5381.2010.00695.x

    authors: Summers RJ

    更新日期:2010-03-01 00:00:00