Publications by authors named "Vahri Beaumont"

22 Publications

  • Page 1 of 1

Phosphodiesterase 9A Inhibition Facilitates Corticostriatal Transmission in Wild-Type and Transgenic Rats That Model Huntington's Disease.

Front Neurosci 2020 3;14:466. Epub 2020 Jun 3.

Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.

Huntington's disease (HD) results from abnormal expansion in CAG trinucleotide repeats within the HD gene, a mutation which leads to degeneration of striatal medium-sized spiny neurons (MSNs), deficits in corticostriatal transmission, and loss of motor control. Recent studies also indicate that metabolism of cyclic nucleotides by phosphodiesterases (PDEs) is dysregulated in striatal networks in a manner linked to deficits in corticostriatal transmission. The current study assessed cortically-evoked firing in electrophysiologically-identified MSNs and fast-spiking interneurons (FSIs) in aged (9-11 months old) wild-type (WT) and BACHD transgenic rats (TG5) treated with vehicle or the selective PDE9A inhibitor PF-04447943. WT and TG5 rats were anesthetized with urethane and single-unit activity was isolated during low frequency electrical stimulation of the ipsilateral motor cortex. Compared to WT controls, MSNs recorded in TG5 animals exhibited decreased spike probability during cortical stimulation delivered at low to moderate stimulation intensities. Moreover, large increases in onset latency of cortically-evoked spikes and decreases in spike probability were observed in FSIs recorded in TG5 animals. Acute systemic administration of the PDE9A inhibitor PF-04447943 significantly decreased the onset latency of cortically-evoked spikes in MSNs recorded in WT and TG5 rats. PDE9A inhibition also increased the proportion of MSNs responding to cortical stimulation and reversed deficits in spike probability observed in TG5 rats. As PDE9A is a cGMP specific enzyme, drugs such as PF-04447943 which act to facilitate striatal cGMP signaling and glutamatergic corticostriatal transmission could be useful therapeutic agents for restoring striatal function and alleviating motor and cognitive symptoms associated with HD.
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http://dx.doi.org/10.3389/fnins.2020.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283904PMC
June 2020

Enhanced striatopallidal gamma-aminobutyric acid (GABA) receptor transmission in mouse models of huntington's disease.

Mov Disord 2019 05 6;34(5):684-696. Epub 2019 Feb 6.

Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Background: Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin gene. This mutation leads to progressive dysfunction that is largely attributable to dysfunction of the striatum. The earliest signs of striatal pathology in HD are found in indirect pathway gamma-Aminobutyric acid (GABA)-ergic spiny projection neurons that innervate the external segment of the globus pallidus (GPe). What is less clear is whether the synaptic coupling of spiny projection neurons with GPe neurons changes in HD.

Objectives: The principal goal of this study was to determine whether striatopallidal synaptic transmission was altered in 2 mouse models of HD.

Methods: Striatopallidal synaptic transmission was studied using electrophysiological and optogenetic approaches in ex vivo brain slices from 2 HD models: Q175 heterozygous (het) and R6/2 mice.

Results: Striatopallidal synaptic transmission increased in strength with the progression of behavioral deficits in Q175 and R6/2 mice. The alteration in synaptic transmission was evident in both prototypical and arkypallidal GPe neurons. This change did not appear attributable to an increase in the probability of GABA release but, rather, to an enhancement in the postsynaptic response to GABA released at synaptic sites. This alteration significantly increased the ability of striatopallidal axon terminals to pause ongoing GPe activity.

Conclusions: In 2 mouse models of HD, striatopallidal synaptic transmission increased in parallel with the progression of behavioral deficits. This adaptation could compensate in part for the concomitant deficit in the ability of corticostriatal signals to activate spiny projection neurons and pause GPe activity. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27622DOI Listing
May 2019

In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [F]MNI-659.

Brain Res 2019 05 18;1711:140-145. Epub 2019 Jan 18.

CHDI Foundation/CHDI Management, Inc., Princeton, NY, USA.

Highly specific and sensitive biomarkers for pathologies related to dysfunctions in the basal ganglia circuit are of great value to assess therapeutic efficacy not only clinically to establish an early diagnosis, but also in terms of monitoring the efficacy of therapeutic interventions and decelerated neurodegeneration. The phosphodiesterase 10A (PDE10A) enzyme plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders involving striatal pathology, such as Huntingtońs disease (HD) and schizophrenia. Inhibition of PDE10A activates the neurons in the striatum and consequently leads to alteration of behavioral aspects modulated by the striatal circuit. [F]MNI-659, (2-(2-(3-(4-(2-[F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), is a newly developed PET radioligand that shows a high binding to PDE10A in the human brain in vivo. In the present study, we examined the in vitro binding of [F]MNI-659 in human postmortem brain to gain a better understanding of the presence, density, disease-related alterations and therapy related to changes in PDE10A expression. The results show high specific binding of [F]MNI-659 in the caudate nucleus, putamen and the hippocampal formation. Low specific [F]MNI-659 binding was detected in nucleus accumbens in comparison to the caudate nucleus and putamen. In vitro binding studies with [F]MNI-659 will facilitate in elucidating better understanding of the role of PDE10A activity in health and disease that may lead to new diagnostic opportunities in HD.
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http://dx.doi.org/10.1016/j.brainres.2019.01.021DOI Listing
May 2019

Age- and sex-related changes in cortical and striatal nitric oxide synthase in the Q175 mouse model of Huntington's disease.

Nitric Oxide 2019 02 5;83:40-50. Epub 2018 Dec 5.

Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.

In Huntington's disease (HD), corticostriatal and striatopallidal projection neurons preferentially degenerate as a result of mutant huntingtin expression. Pathological deficits in nitric oxide (NO) signaling have also been reported in corticostriatal circuits in HD, however, the impact of age and sex on nitrergic transmission is not well characterized. Thus, we utilized NADPH-diaphorase (NADPH-d) histochemistry and qPCR assays to assess neuronal NO synthase (nNOS) activity/expression in aged male and female Q175 heterozygous mice. Compared to age-matched controls, male Q175 mice exhibited reductions in NADPH-d staining in the motor cortex at 21, but not, 16 months of age. Comparisons across genotypes showed that striatal NADPH-d staining was significantly decreased at both 16 and 21 months of age. Comparisons within sexes in 21 month old mice revealed a decrease in striatal NADPH-d staining in males, but no changes were detected in females. Significant correlations between cortical and striatal NADPH-d staining deficits were also observed in males and females at both ages. To directly assess the role of constitutively active NOS isoforms in these changes, nNOS and endothelial NOS (eNOS) mRNA expression levels were examined in R6/2 (3 month old) and Q175 (11.5 month old) mice using qPCR assays. nNOS transcript expression was decreased in the cortex (40%) and striatum (54%) in R6/2 mice. nNOS mRNA down-regulation in striatum of Q175 animals was more modest (19%), and no changes were detected in cortex. eNOS expression was not changed in the cortex or striatum of Q175 mice. The current findings point to age-dependent deficits in nNOS activity in the HD cortex and striatum which appear first in the striatum and are more pronounced in males. Together, these observations and previous studies indicate that decreases in nitrergic transmission progress with age and are likely to contribute to corticostriatal circuit pathophysiology particularly in male patients with HD.
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http://dx.doi.org/10.1016/j.niox.2018.12.002DOI Listing
February 2019

Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor.

Bioorg Med Chem Lett 2019 01 13;29(1):83-88. Epub 2018 Nov 13.

CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, CA 90045, United States.

We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC levels for ∼8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2018.11.009DOI Listing
January 2019

Unravelling and Exploiting Astrocyte Dysfunction in Huntington's Disease.

Trends Neurosci 2017 07 31;40(7):422-437. Epub 2017 May 31.

Exzellenzcluster NeuroCure & Abt. Experimentelle Neurologie, Charité - Universitätsmedizin Berlin, Robert-Koch-Platz 4, D-10115 Berlin, Germany.

Astrocytes are abundant within mature neural circuits and are involved in brain disorders. Here, we summarize our current understanding of astrocytes and Huntington's disease (HD), with a focus on correlative and causative dysfunctions of ion homeostasis, calcium signaling, and neurotransmitter clearance, as well as on the use of transplanted astrocytes to produce therapeutic benefit in mouse models of HD. Overall, the data suggest that astrocyte dysfunction is an important contributor to the onset and progression of some HD symptoms in mice. Additional exploration of astrocytes in HD mouse models and humans is needed and may provide new therapeutic opportunities to explore in conjunction with neuronal rescue and repair strategies.
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http://dx.doi.org/10.1016/j.tins.2017.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706770PMC
July 2017

Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models.

Neuron 2016 Dec 1;92(6):1220-1237. Epub 2016 Dec 1.

CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, CA 90045, USA.

Huntington's disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2016.10.064DOI Listing
December 2016

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease.

Exp Neurol 2016 08 6;282:99-118. Epub 2016 May 6.

CHDI Foundation/CHDI Management Inc., Los Angeles, USA. Electronic address:

Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD). In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), an enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. In order to determine the role of KMO in the phenotype of mouse models of HD, we have developed a potent and selective KMO inhibitor termed CHDI-340246. We show that this compound, when administered orally to transgenic mouse models of HD, potently and dose-dependently modulates the Kyn pathway in peripheral tissues and in the central nervous system. The administration of CHDI-340246 leads to an inhibition of the formation of 3-OH-Kyn and Quin, and to an elevation of Kyn and Kynurenic acid (KynA) levels in brain tissues. We show that administration of CHDI-340246 or of Kyn and of KynA can restore several electrophysiological alterations in mouse models of HD, both acutely and after chronic administration. However, using a comprehensive panel of behavioral tests, we demonstrate that the chronic dosing of a selective KMO inhibitor does not significantly modify behavioral phenotypes or natural progression in mouse models of HD.
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http://dx.doi.org/10.1016/j.expneurol.2016.05.005DOI Listing
August 2016

Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis).

PLoS One 2014 22;9(7):e102449. Epub 2014 Jul 22.

CHDI Foundation/CHDI Management Inc., Los Angeles, California, United States of America.

Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102449PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106781PMC
March 2016

The PDE1/5 Inhibitor SCH-51866 Does Not Modify Disease Progression in the R6/2 Mouse Model of Huntington's Disease.

PLoS Curr 2014 Feb 13;6. Epub 2014 Feb 13.

CHDI Management/CHDI Foundation, Los Angeles, California, USA.

Huntington's disease is a neurodegenerative disorder caused by mutations in the CAG tract of huntingtin. Several studies in HD cellular and rodent systems have identified disturbances in cyclic nucleotide signaling, which might be relevant to pathogenesis and therapeutic intervention. To investigate whether selective phosphodiesterase (PDE) inhibitors can improve some aspects of disease pathogenesis in HD models, we have systematically evaluated the effects of a variety of cAMP and cGMP selective PDE inhibitors in various HD models. Here we present the lack of effect in a variety of endpoints of the PDE subtype selective inhibitor SCH-51866, a PDE1/5 inhibitor, in the R6/2 mouse model of HD, after chronic oral dosing.
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http://dx.doi.org/10.1371/currents.hd.3304e87e460b4bb0dc519a29f4decccaDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923778PMC
February 2014

HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.

PLoS Biol 2013 Nov 26;11(11):e1001717. Epub 2013 Nov 26.

Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.

Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine-rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein-folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion in the huntingtin protein. We found that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels, and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor coordination, neurological phenotypes, and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for the cytoplasmic aggregation process in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation, which may be amenable to small-molecule therapeutics.
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http://dx.doi.org/10.1371/journal.pbio.1001717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841096PMC
November 2013

HDAC4 does not act as a protein deacetylase in the postnatal murine brain in vivo.

PLoS One 2013 22;8(11):e80849. Epub 2013 Nov 22.

Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.

Reversible protein acetylation provides a central mechanism for controlling gene expression and cellular signaling events. It is governed by the antagonistic commitment of two enzymes families: the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). HDAC4, like its class IIa counterparts, is a potent transcriptional repressor through interactions with tissue specific transcription factors via its N-terminal domain. Whilst the lysine deacetylase activity of the class IIa HDACs is much less potent than that of the class I enzymes, HDAC4 has been reported to influence protein deacetylation through its interaction with HDAC3. To investigate the influence of HDAC4 on protein acetylation we employed the immunoaffinity-based AcetylScan proteomic method. We identified many proteins known to be modified by acetylation, but found that the absence of HDAC4 had no effect on the acetylation profile of the murine neonate brain. This is consistent with the biochemical data suggesting that HDAC4 may not function as a lysine deacetylase, but these in vivo data do not support the previous report showing that the enzymatic activity of HDAC3 might be modified by its interaction with HDAC4. To complement this work, we used Affymetrix arrays to investigate the effect of HDAC4 knock-out on the transcriptional profile of the postnatal murine brain. There was no effect on global transcription, consistent with the absence of a differential histone acetylation profile. Validation of the array data by Taq-man qPCR indicated that only protamine 1 and Igfbp6 mRNA levels were increased by more than one-fold and only Calml4 was decreased. The lack of a major effect on the transcriptional profile is consistent with the cytoplasmic location of HDAC4 in the P3 murine brain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080849PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838388PMC
December 2014

Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease.

J Med Chem 2013 Dec 5;56(24):9934-54. Epub 2013 Dec 5.

BioFocus , Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, United Kingdom.

Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.
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http://dx.doi.org/10.1021/jm4011884DOI Listing
December 2013

Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease.

PLoS One 2012 20;7(12):e50717. Epub 2012 Dec 20.

Charles River Discovery Research Services, Kuopio, Finland.

Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT) mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI) mouse, was developed (see description by Menalled et al, [1]) in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al [1], and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo- and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic strategies to slow the progression of disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050717PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527436PMC
June 2013

Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo.

PLoS One 2012 4;7(9):e44498. Epub 2012 Sep 4.

CHDI Management/CHDI Foundation Inc., Los Angeles, California, United States of America.

Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044498PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433414PMC
January 2013

Striatal pre- and postsynaptic profile of adenosine A(2A) receptor antagonists.

PLoS One 2011 Jan 11;6(1):e16088. Epub 2011 Jan 11.

National Institute on Drug Abuse, IRP, NIH, DHHS, Baltimore, Maryland, United States of America.

Striatal adenosine A(2A) receptors (A(2A)Rs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D(2) receptors (D(2)Rs). A(2A)Rs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A(1) receptors (A(1)Rs). It has been hypothesized that postsynaptic A(2A)R antagonists should be useful in Parkinson's disease, while presynaptic A(2A)R antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A(2A)R antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A(2A)R-D(2)R and A(1)R-A(2A)R heteromers to determine possible differences in the affinity of these compounds for different A(2A)R heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A(2A)R when co-expressed with D(2)R than with A(1)R. KW-6002 showed the best relative affinity for A(2A)R co-expressed with D(2)R than co-expressed with A(1)R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential pre- versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016088PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019225PMC
January 2011

Evidence for an enhancement of excitatory transmission in adult CNS by Wnt signaling pathway modulation.

Mol Cell Neurosci 2007 Aug 14;35(4):513-24. Epub 2007 Mar 14.

The Neuroscience Research Centre, Merck Sharp and Dohme, Terlings Park, Harlow Essex CM20 2QR, UK.

The role for Wnt signaling modulation during synaptogenesis, neurogenesis and cell fate specification have been well characterized. In contrast, the roles for Wnt signaling pathways in the regulation of synaptic plasticity and adult physiology are only starting to be elucidated. Here, we have identified a novel series of Wnt pathway small molecule modulators, and report that these and other small molecules targeting the Wnt pathway acutely enhance excitatory transmission in adult hippocampal preparations. Our findings are consistent with a pre- and postsynaptic site of action, leading to both increased spontaneous and evoked neurotransmission that occurs in a transcription-independent fashion.
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http://dx.doi.org/10.1016/j.mcn.2007.03.004DOI Listing
August 2007

Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications.

Neuropsychopharmacology 2008 Feb 9;33(3):685-700. Epub 2007 May 9.

Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme, The Neuroscience Research Centre, Essex, UK.

The receptor tyrosine kinase product of the anaplastic lymphoma kinase (ALK) gene has been implicated in oncogenesis as a product of several chromosomal translocations, although its endogeneous role in the hematopoietic and neural systems has remained poorly understood. We describe that the generation of animals homozygous for a deletion of the ALK tyrosine kinase domain leads to alterations in adult brain function. Evaluation of adult ALK homozygotes (HOs) revealed an age-dependent increase in basal hippocampal progenitor proliferation and alterations in behavioral tests consistent with a role for this receptor in the adult brain. ALK HO animals displayed an increased struggle time in the tail suspension test and the Porsolt swim test and enhanced performance in a novel object-recognition test. Neurochemical analysis demonstrates an increase in basal dopaminergic signalling selectively within the frontal cortex. Altogether, these results suggest that ALK functions in the adult brain to regulate the function of the frontal cortex and hippocampus and identifies ALK as a new target for psychiatric indications, such as schizophrenia and depression, with an underlying deregulated monoaminergic signalling.
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http://dx.doi.org/10.1038/sj.npp.1301446DOI Listing
February 2008

Expansion of calcium microdomains regulates fast exocytosis at a ribbon synapse.

Proc Natl Acad Sci U S A 2005 Jul 18;102(30):10700-5. Epub 2005 Jul 18.

Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom.

We investigated the Ca2+ signal regulating fast exocytosis at the ribbon synapse of retinal bipolar cells by using total internal reflection fluorescence microscopy to image fluorescent Ca2+ indicators and interference reflection microscopy to monitor exocytosis. Depolarization generated Ca2+ "microdomains" that expanded over the time scale during which the rapidly releasable pool (RRP) of vesicles was released (<40 ms). Replacing mobile Ca2+ buffers in the terminal with 10 mM EGTA prevented expansion of microdomains and decreased the number of rapidly releasable vesicles by a factor of 2. Conversely, decreasing the concentration of EGTA in the terminal to 0.1 mM increased the apparent width of a Ca2+ microdomain from 580 nm to 930 nm and increased the size of the RRP size by a factor of 1.5. The [Ca2+] over the area that the microdomain expanded was estimated to be 2-7 microM. These results indicate that vesicles within the RRP are located hundreds of nanometers from Ca2+ channels, and that fusion of these vesicles can be triggered by low micromolar levels of Ca2+. Variable distances between docked vesicles and Ca2+ channels at the active zone, therefore, provide an explanation for the heterogeneous release probability of vesicles comprising the RRP.
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http://dx.doi.org/10.1073/pnas.0501961102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1180766PMC
July 2005

Calcium influx through HCN channels does not contribute to cAMP-enhanced transmission.

J Neurophysiol 2004 Jul 10;92(1):644-7. Epub 2004 Mar 10.

Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, 111 Life Sciences Addition, Berkeley, CA 94720-3200, USA.

Serotonin is a native neuromodulator of synaptic transmission at glutamatergic neuromuscular junctions of crayfish limb muscles. During times of stress, serotonin binds to presynaptic receptors, which activate adenylyl cyclase to elevate presynaptic levels of cAMP. cAMP binds to two presynaptic target proteins, hyperpolarization and cyclic nucleotide-activated (HCN) ion channels and an exchange protein activated by cAMP (Epac), and activation of these effectors results in enhancement of transmitter release to action potentials. cAMP elevation also results in a small preterminal rise in [Ca(2+)](i), which we show here to result from Ca(2+) influx through the presynaptic HCN channels opened by cAMP. Little or no Ca(2+) influx occurs through voltage-dependent Ca(2+) channels, despite the small presynaptic depolarization caused by current through the HCN channels. Loading terminals with BAPTA delays the rise in preterminal [Ca(2+)](i) without affecting the enhancement of transmission to cAMP elevation. This dissociation of the dynamics of the [Ca(2+)](i) rise and synaptic enhancement, plus the small magnitude and location of [Ca(2+)](i) elevation distant from release sites, seems to preclude any direct role for this [Ca(2+)](i) elevation in cAMP-dependent enhancement of transmission.
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http://dx.doi.org/10.1152/jn.00112.2004DOI Listing
July 2004

Real-time measurement of exocytosis and endocytosis using interference of light.

Neuron 2003 Dec;40(6):1075-86

MRC Laboratory of Molecular Biology, Hills Road, CB2 2QH, Cambridge, United Kingdom.

We describe a new approach for making real-time measurements of exocytosis and endocytosis in neurons and neuroendocrine cells. The method utilizes interference reflection microscopy (IRM) to image surface membrane in close contact with a glass coverslip (the "footprint"). At the synaptic terminal of retinal bipolar cells, the footprint expands during exocytosis and retracts during endocytosis, paralleling changes in total surface area measured by capacitance. In chromaffin cells, IRM detects the fusion of individual granules as the appearance of bright spots within the footprint with spatial and temporal resolution similar to total internal reflection fluorescence microscopy. Advantages of IRM over capacitance are that it can monitor changes in surface area while cells are electrically active and it can be applied to mammalian neurons with relatively small synaptic terminals. IRM reveals that vesicles at the synapse of bipolar cells rapidly collapse into the surface membrane while secretory granules in chromaffin cells do not.
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http://dx.doi.org/10.1016/s0896-6273(03)00765-7DOI Listing
December 2003

Temporal synaptic tagging by I(h) activation and actin: involvement in long-term facilitation and cAMP-induced synaptic enhancement.

Neuron 2002 Feb;33(4):601-13

Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.

Presynaptic I(h) channels become activated during a tetanus through membrane hyperpolarization resulting from Na(+) accumulation and electrogenic Na(+)/K(+) exchange. I(h) activation is obligatory for inducing long-term facilitation (LTF), a long-lasting synaptic strengthening. cAMP-induced synaptic enhancement also requires I(h) activation, and both processes are sensitive to actin depolymerization. Other mechanisms are responsible for expression of the responses. Once initiated, continued response to cAMP is I(h) and actin independent. Moreover, LTF-induced activation of I(h) renders subsequent cAMP enhancement insensitive to both I(h) blockers and actin depolymerization. This actin-stabilized "temporal synaptic tagging" set by I(h) activation is prolonged when I(h) is activated concurrent with an elevation in presynaptic calcium concentration ([Ca(2+)]i), permitting the further strengthening of synapses given appropriate additional stimuli.
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http://dx.doi.org/10.1016/s0896-6273(02)00581-0DOI Listing
February 2002