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Parkinson's Disease
Volume 2013 (2013), Article ID 196028, 11 pages
Metabotropic Glutamate Receptors for Parkinson's Disease Therapy
1Novartis Pharma AG, Novartis Institutes for BioMedical Research Basel, Forum 1, Novartis Campus, 4056 Basel, Switzerland
2Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, QC, Canada G1V 4G2
3Faculty of Pharmacy, Laval University, Quebec City, QC, Canada G1K 7P4
Received 17 March 2013; Accepted 29 May 2013
Academic Editor: Francisco Grandas
Copyright © 2013 Fabrizio Gasparini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinson's disease (PD) and inthe emergence of dyskinesia associated with long-term treatment with L-DOPA. There is considerable research focus on the discovery and development of compounds that modulate glutamatergic signalling via glutamate receptors, as treatments for PD and L-DOPA-induced dyskinesia (LID). Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects, with the exception of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, currently used to reduce dyskinesia in PD patients. Metabotropic receptor (mGlu receptor) modulators were considered to have a more favourable side-effect profile, and several agents have been studied in preclinical models of PD. The most promising results have been seen clinically with selective antagonists of mGlu5 receptor and preclinically with selective positive allosteric modulators of mGlu4 receptor. The growing understanding of glutamate receptor crosstalk also raises the possibility of more precise modulation of glutamatergic transmission, which may lead to the development of more effective agents for PD.
1. Introduction
Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder of the central nervous system (CNS), characterised by a gradual loss of dopaminergic neurotransmission. Cardinal symptoms of PD include tremor, bradykinesia, and rigidity. Levodopa (L-DOPA) is considered the standard of care for providing symptomatic relief in PD [1]. However, long-term L-DOPA treatment leads to the appearance of motor complications in the majority of responding patients and severely affects their quality of life [2]. After 9 years of L-DOPA treatment, ~90% of PD patients experience dyskinesia [3]. The dyskinesia that develops is often a combination of choreic and dystonic abnormal involuntary movements, collectively termed L-DOPA-induced dyskinesia (PD-LID).
Once PD-LID is established, increasing the L-DOPA dose typically worsens dyskinesia and this may prevent the use of L-DOPA at optimal doses required to control motor fluctuations. There are currently no licensed therapies for the treatment of PD-LID, although a number of clinical strategies are employed including adding dopamine agonists, monoamine oxidase inhibitors, adenosine (2A) receptor antagonists, catechol-O-methyl transferase inhibitors, and anticholinergic drugs as part of a L-DOPA-sparing strategy [4–7] and the use of amantadine [8]; see Tambasco et al. 2012 for a recent review [9].
The precise mechanisms of PD-LID are not completely understood, but excessive glutamatergic transmission within the basal-ganglia is thought to play a key role in the pathophysiology of PD and PD-LID [10, 11]. Therefore, therapeutic agents that regulate glutamate transmission are valid targets for drug development to alleviate motor symptoms associated with PD and PD-LID (Table 1). In this paper we will review attempts to develop therapeutic agents capable of normalising defective glutamatergic transmission via modulation of glutamate receptors.
2. Basal Ganglia Circuitry in Parkinson's Disease
A balance between inhibition and excitation of the major output nuclei of the basal ganglia is important for normal motor control. This is achieved via direct and indirect inhibitory projections (GABAergic) from the striatum (caudate nucleus/putamen) to the globus pallidus internal (GPi)/substantia nigra pars reticulate (SNr) and excitatory projections (glutamatergic) from the subthalamic nucleus (STN) to the substantia nigra pars compacta (SNc) and GPi/SNr. Appropriate dopaminergic input from the SNc to the striatum plays a key role in maintaining this balance [12]. In patients with PD, degeneration of dopamine nigral neurons within the SNc results in loss of dopaminergic modulation and increases the overall excitatory drive in the basal ganglia, disrupting voluntary motor control and causing the characteristic symptoms of PD [13]. The progressive depletion of the endogenous dopaminergic signalling combined with the compensatory exogenous supply of dopamine (DA) precursor L-DOPA induces profound changes in the neurotransmitter network of the basal ganglia [14]. An imbalance in the DA receptors, particularly between D1 and D2 receptor subtypes mainly expressed in the direct and indirect striatal output pathways, respectively, has been identified in dyskinetic nonhuman primates [15, 16]. In rodents, genetic ablation of the D1 receptor subtype but not the D2 subtype abolished the L-DOPA-induced dyskinesia. These results suggest a key role for the D1 receptor in the development of PD-LID [16]. However, a role for D2 receptors in the onset and expression of L-DOPA induced dyskinesias is also documented [17]. Additional changes in other dopamine receptor subtypes such as D3 and D5 have also been identified [18].
The cellular mechanisms by which the dopaminergic neurons are lost are not fully understood, although excessive glutamatergic transmission has been implicated [19, 20]. Glutamate is the main excitatory neurotransmitter in the CNS and normal brain function requires balanced glutamatergic neurotransmission. As a result of striatal dopaminergic denervation, the glutamatergic projections from the STN to the basal ganglia output nuclei become overactive with reduced regulation of glutamate receptors [19]. The resultant excessive excitation by glutamate through the basal ganglia circuitry can be toxic to any remaining dopaminergic neurons, leading to further loss of dopaminergic transmission and progression of PD symptoms [21]. Normalisation of motor function is initially seen with L-DOPA treatment. However, as the severity of PD increases, the substantial dopaminergic depletion leads to further adaptive changes in the basal ganglia pathways, including altered function of nondopaminergic basal ganglia neurotransmitters, such as glutamate, GABA, and serotonin [22]. Advanced nigral cell degeneration is considered responsible for the priming of the basal ganglia, as dyskinesia develops rapidly in monkeys with drug-induced nigral denervation following L-DOPA treatment [13], whereas L-DOPA treatment alone in animal models or healthy humans does not induce dyskinesia [23, 24]. Further evidence for a role for excessive glutamate transmission in PD and PD-LID comes from the clinical use of amantadine, a weak antagonist of NMDA glutamate receptors, in the treatment of PD-LID. To reduce the effects of the excessive glutamatergic transmission, several approaches aiming to modulate the glutamate receptors are available. These different approaches are dependent on the localisation and the function of each receptor subtype as illustrated on Figure 1 and will be described in the following sections.
3. Glutamate Receptors in Parkinson's Disease
Glutamate receptors modulate glutamatergic neurotransmission in the brain and play a role in memory, learning and motor control; glutamatergic dysfunction is implicated in a range of neurological disorders [25–27]. Two classes of glutamate receptor have been described: ionotropic glutamate receptors (iGlu receptors) [28], and metabotropic glutamate receptors (mGlu receptors) [26].
3.1. Ionotropic Glutamate Receptors.
iGlu receptors are ligand-gated ion channels composed of four large subunits that form a central pore within the cell membrane. The iGlu receptors include the NMDA (N-methyl-d-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate ([2S,3S,4S]-3-[carboxymethyl]-4-prop-1-en-2-yl-pyrrolidine-2-carboxylic acid) receptors, all of which share a similar structure but differ in their amino acid sequences, subunit combination, and agonist sensitivity/selectivity. Within the CNS, iGlu receptors are responsible for fast excitatory transmission [28]. Their important role in mediating glutamatergic neurotransmission identifies the iGlu receptors as potential therapeutic targets for symptomatic management in PD and PD-LID.
3.1.1. AMPA Receptors
Within the mammalian CNS, the majority of fast excitatory synaptic transmission is mediated by AMPA receptors [29]. AMPA receptor function is critical for synaptic plasticity. The potential for therapeutic AMPA modulation for PD is yet to be conclusively proven. Preclinical studies of AMPA receptor antagonists 6-nitro-sulfamoyl-benzo-quinoxaline-dione (NBQX) and GYKI-52466 failed to show antiparkinsonian activity when they were administered alone [30–34]. NBQX has shown some antiparkinsonian activity in another study where it reversed reserpine-induced muscle rigidity, but not akinesia in monoamine-depleted rats, and motor deficits in MPTP-lesioned Rhesus monkeys [35]. In another study, NBQX was combined with the competitive NMDA receptor antagonist 3-carboxy- piperazin-propyl phosphonic acid (CPP) and reversed the shortened duration of L-DOPA-induced motor responses [36]. Interestingly, NBQX [31, 32, 34] and CPP [30, 31] both potentiate the antiparkinsonian effects of coadministered dopaminergic agents. L-DOPA-sparing effects have also been shown in preclinical models with GYKI-52466 and GYKI-53405 [37, 38].
Increased AMPA receptor activity has been implicated in the development of LID [11, 39]. The competitive AMPA/kainate receptor antagonist LY293558 (tezampanel) reversed and prevented LID in parkinsonian rats [40] and the noncompetitive AMPA/kainate antagonist LY300164 (talampanel) decreased LID in MPTP-treated monkeys by up to 40% [41]. Another non-competitive AMPA receptor antagonist, perampanel, showed promising results in preclinical studies, reducing L-DOPA-induced motor defects 6-OHDA-primed rats [42] and dyskinesia in MPTP-treated monkeys [43]. Unfortunately, these results have not successfully translated to the clinical setting, and initial phase II and III trials of perampanel were terminated because of lack of efficacy [44–46].
3.1.2. NMDA Receptors
NMDA receptors mediate glutamatergic excitation in the striatum and STN; NMDA-mediated signalling in the brain is thought to be involved in both neural plasticity and neurotoxicity [24]. Dysfunctions in NMDA receptor trafficking in striatal neurons result in the altered synaptic plasticity seen in animal models of PD and dyskinesia [47]. Several antagonists of NMDA receptors have shown therapeutic potential in animal models of PD: neuroprotective activity, by limiting the extent of nigrostriatal damage [48], or behavioural effects through the improvement of motor symptoms of PD [49, 50] and preventing or reducing LID [51–55]. Administration of competitive NMDA receptor antagonists such as CPP, CGP-43487, and APV, which target the glutamate binding site, or PAMQX, which binds to the glycine site in NMDA heterodimers, has also been shown to potentiate dopaminergic therapies in preclinical PD models [34, 56, 57]. There is also evidence of synergism between AMPA and NMDA antagonists in animal models of PD and LID [31, 58]. Further evidence of crosstalk between receptors involved in PD pathophysiology comes from studies showing interactions with 5-HT (2A) receptors [59, 60] and adenosine (2A) receptors in animal models [61], raising the possibility of adenosine (2A) or 5-HT (2A) receptor modulation as a novel therapeutic strategy for PD. NR2B-selective, non-competitive NMDA receptor antagonists, tnaxoprodil and ifenprodil, have shown therapeutic potential in animal models of PD-LID [50, 52, 62, 63].
Despite positive results in preclinical studies, clinical development of NMDA antagonists has been hampered by the side effects of these compounds, including psychosis, impaired learning, and disruption of motor function [64], which pose substantial problems with chronic use. This observed absence of a therapeutic window is likely due to the wide expression of NMDA receptors throughout the CNS and their key involvement in many physiological processes.
The greatest success with NMDA antagonists in PD and PD-LID has been seen with amantadine, a weak non-competitive NMDA receptor antagonist. Amantadine is approved for the treatment of PD and is widely used to treat PD-LID (off-label indication), due to its inclusion in international guidelines [65, 66]. Antidyskinetic activity with amantadine has been reported in both 6-OHDA rodent and MPTP primate models of LID [60, 67, 68]. Clinical benefits with amantadine in PD-LID have been seen in an increasing number of clinical trials [69–74] and the benefits appear to be long lasting [75, 76]. An extended-release formulation of amantadine, amantadine ER (ADS–5102), is currently in clinical trials for PD-LID. Other non-competitive NMDA receptor antagonists that have been investigated in the clinical setting include remacemide, which has failed to show benefit in the symptomatic management of PD and LIDs [77–80]. The non-competitive NMDA receptor antagonist, traxoprodil has shown clinical efficacy in two small studies [81, 82].
3.1.3. Kainate Receptors
The existence of kainate receptors has been known for some time, yet little is understood about the contribution to the pathology of PD or the potential of kainate receptors as therapeutic targets in PD and PD-LID. This is primarily due to a lack of selective pharmacological agents to help elucidate the complex molecular mechanisms underlying these conditions.
3.2. Metabotropic Glutamate Receptors
The limitations of targeting iGlu receptors in PD combined with the high expression of mGlu receptors in the basal ganglia and their diverse modulatory roles has raised the interest in mGlu receptors as alternative targets for modulating glutamate hyperactivity in PD [12, 27]. mGlu receptors belong to the G-protein-coupled receptor family and are membrane-bound and activated by extracellular ligands. Unlike the fast excitatory glutamatergic transmission mediated by iGlu receptors, mGlu receptors have a more modulatory role, responsible for fine tuning glutamatergic transmission [26]. Eight mGlu receptor subtypes have been cloned and classified into three groups according to sequence similarity, signal transduction mechanism, and pharmacological properties [26]. Group I (mGlu1 and 5) receptors are coupled to activation of phospholipase C and mediate postsynaptic excitatory effects. They are mainly located postsynaptically and modulate glutamate transmission through negative and positive regulation of potassium and calcium ion channels, respectively. Group II (mGlu2 and 3) and Group III (mGlu4, 6, 7, and 8) receptors are negatively coupled to adenyl cyclase and inhibit cAMP formation. Both groups are generally located presynaptically and inhibit neurotransmitter release primarily through modulation of calcium and potassium ion channels. Of these 8 subtypes, mGlu5 and mGlu4 receptors are of particular interest as therapeutic targets in PD given their expression and distribution in the basal ganglia.
3.2.1. Group I mGlu Receptors
Group I receptors mGlu1 and 5 share a high degree of sequence homology but their expression patterns within the brain differ considerably (Figure 2), suggesting that they may have distinct functional roles in brain physiology and pathophysiology.
The role of mGlu1 receptor in PD and PD-LID was examined using the selective antagonist, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methane sulfonate (EMQMCM), in 6-OHDA primed rats [83]. Treatment with EMQMCM induced some improvement of dyskinesia, altered downstream molecular signalling pathways, and attenuated L-DOPA-induced gene expression. However, these effects were achieved at a dose which blocked the antiakinetic (antiparkinsonian) action of L-DOPA. Together, these data do not support the use of mGlu1 receptor antagonists as a treatment for PD-LID.
The high expression of mGlu5 receptor in the caudate nuclei, putamen and basal ganglia [85, 86], and its postsynaptic localisation, make the mGlu5 receptor an attractive target to modulate the excessive glutamatergic neurotransmission induced by the loss of dopaminergic innervation. The first attempts to inhibit the mGlu5 receptor were made with competitive and nonselective antagonists. These early tool compounds had poor in vivo properties and brain penetration resulting in an inability to identify a role for the mGlu5 receptor. The identification and use of more specific tool compounds such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP) enabled the hypothesis to be tested in various animal models of PD. The first confirmation of the potential to modulate excessive glutamatergic neurotransmission via inhibition of mGlu5 receptor came from the work of Spooren et al. [87]. They showed that MPEP could attenuate unilateral rotating behaviour in the rat 6-hydroxydopamine (6-OHDA) lesion model. Shortly after, Breysse et al. [88] provided further supportive data, by showing how chronic (but not acute) treatment with MPEP could improve akinesia in the 6-OHDA rat model. However, in this study no effects on haloperidol-induced catalepsy were observed following MPEP treatment [88]. In rats with nigrostriatal lesions, MPEP virtually abolished abnormal involuntary movements [89]. Using 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]pyridine (MTEP), which has superior specificity and bioavailability to MPEP, a reduction of haloperidol-induced catalepsy and muscle rigidity in rats was seen [90].
More recently, mGlu5 receptor expression was shown to be enhanced within the posterior putamen and globus pallidus of parkinsonian monkeys experiencing dyskinesia following chronic L-DOPA treatment [91] and in human postmortem brains of parkinsonian patients with dyskinesia and wearing off [92]. In addition, animal models of PD-LID show upregulation of mGlu5 receptor genes, reflecting long-term changes associated with the development of dyskinesia [93]. There is also evidence of crosstalk between mGlu5 receptors and NMDA receptors in the striatum and subthalamic nucleus [94, 95], and it is possible that therapeutic modulation of mGlu5 receptors may have beneficial effects on NMDA receptor signalling in PD. Additionally, mGlu5 receptors and adenosine A (2A) receptors are coexpressed in D2 striatal neurons and interact to regulate the downstream effects of mGlu5 receptor activity [96–99].
The first evidence for the therapeutic potential of mGlu5 antagonists in PD-LID was presented by Hill et al. [100] using the noncompetitive antagonist, SIB-1893, to ease LIDs in MPTP-lesioned monkeys. Interestingly, SIB-1893 was identified initially as a relatively weak mGlu5 receptor antagonist (IC50 = 2.3 μM) [101], whereas further characterisation revealed SIB-1893 to also be a positive allosteric modulator (PAM) of the mGlu4 receptor [102].
The use of MTEP confirmed that antagonism of mGlu5 receptor attenuates LID in 6-OHDA lesioned rats [103, 104] and MPTP-lesioned monkeys [105]. In MPTP-lesioned monkeys, MPEP showed antiparkinsonian effects and reduced the development of LID [106]. Similar results were seen with both MPEP and MTEP in MPTP-lesioned monkeys treated with L-DOPA [105]. Other selective mGlu5 receptor antagonists that have shown preclinical anti-dyskinetic effects include 6,6-dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one (MRZ-8676) [100], dipraglurant (ADX48621; Addex Press Release), and mavoglurant (AFQ056), which reduced dyskinesia in L-DOPA-treated MPTP-lesioned monkeys [100]. In addition, mavoglurant did not adversely affect the response to L-DOPA in MPTP-lesioned monkeys, but did potentiate the effects of low doses of L-DOPA [107].
In contrast to other therapeutic approaches in PD, the wealth of preclinical data supporting the potential of mGlu5 receptor antagonists in treating PD and LID has been confirmed clinically by two drug candidates, mavoglurant [108, 109] and dipraglurant [110]. Both have shown significant anti-dyskinetic activity in patients with moderate-to-severe PD-LID. Follow-up trials with both mavoglurant and dipraglurant are ongoing.
3.2.2. Group III mGlu Receptors
Among the Group III mGlu receptors, mGlu4, 7, and 8 are expressed at multiple synapses throughout the basal ganglia and mainly localised presynaptically [12, 85]. Their activation inhibits neurotransmitter release, a mechanism implicated in the pathophysiology of PD [111–113]. Preclinical studies with selective Group III mGlu receptor competitive agonists reversed akinesia and haloperidol-induced catalepsy in rodent models of PD [114–116].
Similarly, PAMs targeting mGlu4 receptor have shown some antiparkinsonian activity in animal models of PD. For example, N-phenyl-7-(hydroxyimino) cyclopropa[b]-chromen-1a-carboxamide (PHCCC) reversed risperidine-induced akinesia in rats [117] and reduced striatal dopamine neuron degeneration in MPTP-treated mice [118]. However, PHCCC has low potency and poor aqueous solubility and demonstrates antagonism at mGlu1 receptors at a similar potency to that at mGlu4 receptors [117]. Therefore, agents exhibiting greater potency and selectivity for mGlu4 receptors have been sought to clarify the therapeutic potential of targeting this receptor subtype in PD. One such agent, VU0155041, has shown antiparkinson activity in haloperidol-induced catalepsy and 6-OHDA lesioned rats [119, 120]. VU0155041 also demonstrated synergy when coadministered with the adenosine (2A) receptor agonist preladenant, as well as L-DOPA, suggesting a potential L-DOPA-sparing mechanism [120]. Similarly, 5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl) thiazol-2-amine (ADX88178), a PAM with high bioavailability and specificity for mGlu4 receptor, has antiparkinsonian activity including potentiation of L-DOPA effects, without increasing LID [121].
Activation of the mGlu7 receptor using the PAM, N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), has also shown antiparkinsonian and antidyskinetic activity in rodent models of PD [12, 122]. Currently, there are no agonists or PAMs, with appropriate oral bioavailability and brain permeability available for targeting the mGlu8 receptor. However, intracerebroventricular injection of the mGlu8 receptor agonist, (S)-3,4-dicarboxyphenylglycine (DCPG), reportedly reversed parkinsonian symptoms in a rat model for PD [123].
3.2.3. Group II mGlu Receptors
Activation of Group II mGlu2 and 3 receptors using competitive agonists has been extensively characterised in animal models. Based on their preclinical profile, these group II agonists have been evaluated in the clinic for anxiety [124] and schizophrenia [125]. In contrast, preclinical data supporting a beneficial effect in PD are limited. Both receptors have been located in key areas of the basal ganglia associated with PD pathophysiology such as the SNr, and their activation is known to inhibit synaptic excitation [85, 126, 127]. However, ligand binding autoradiography in postmortem brain tissue, from MPTP-treated monkeys and patients with PD, suggests that there are no clear changes in the expression of mGlu2 and 3 receptors associated with PD-LID [128, 129]. Systemic administration of the competitive mGlu2/3 receptor agonist LY379268 failed to provide any functional benefit in the 6-OHDA lesioned rat model [130]. Johnson et al. suggested that [131] the lack of subtype specificity and limited brain penetrability of LY379268 were responsible for the absence of efficacy seen following systemic administration [122]. PAMs selective for mGlu2 receptor have an improved pharmacokinetic profile and good brain penetration [123]. In vivo, mGlu2 receptor PAMs have shown that they are valuable alternative to the competitive agonists in a rodent model for panic-like behaviour [132]. Future investigations of PAMs targeting mGlu2 receptors using appropriate animal models will be key to evaluating the potential of this mechanism of action in PD.
4. Conclusions
Nigrostriatal denervation in PD leads to increased glutamatergic transmission in the basal ganglia, which leads to further loss of dopaminergic neurons, progression of PD, and the appearance of PD-LID. Pharmacological modulation of glutamatergic transmission is a key focus for research into novel nondopaminergic agents for PD. Antagonists of iGlu receptors have shown antiparkinsonian and antidyskinetic effects in preclinical studies, but the emergence of adverse effects has limited the clinical value of these agents. Amantadine, a weak NMDA antagonist, is the exception, showing significant anti-dyskinetic effects in the clinical setting. Modulators of mGlu receptors hold greater promise in PD due to their location in the basal ganglia and the development of a number of agents with high potency and selectivity for different mGlu receptor subtypes. In particular, preclinical studies with mGlu5 receptor subtype selective antagonists and PAMs of mGlu4 receptor have shown good efficacy in models of both PD and PD-LID, and there is now growing clinical evidence for mGlu5 receptor antagonism as a valid therapeutic target for PD-LID. Research into glutamate receptor signalling in the basal ganglia is now revealing a hugely complex network involving cross-talk between different glutamate receptors, dopamine, and adenosine receptors. As we understand more about the importance of these interactions, we may be able to develop compounds that can fine tune dopaminergic and non-dopaminergic transmission, leading to better treatments for PD and PD-LID.
Conflict of Interests
Fabrizio Gasparini and Baltazar Gomez-Mancilla are employees of Novartis Pharma AG and hold shares with Novartis Pharma AG. Fabrizio Gasparini and Baltazar Gomez-Mancilla have also received reimbursement from Novartis Pharma AG for travel expenses. The work of Thérèse Di Paolo is supported by funding from the Canadian Institutes of Health Research, The Quebec Consortium for Drug Discovery, and the Natural Sciences and Engineering Research Council of Canada. Thérèse Di Paolo has also received compensation from Novartis Pharma AG for investigating new compounds in vivo as part of a collaborative project and reimbursement for travel expenses. Thérèse Di Paolo is also coauthor on patents with Novartis Pharma AG.
Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. The authors would like to thank Kerrie O'Rourke, Ph.D., and Georgina Collett, Ph.D., of iMed Comms, who provided medical writing assistance with this paper.
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- B. Greco, S. Lopez, H. Van Der Putten, P. J. Flor, and M. Amalric, "Metabotropic glutamate 7 receptor subtype modulates motor symptoms in rodent models of Parkinson's disease," Journal of Pharmacology and Experimental Therapeutics, vol. 332, no. 3, pp. 1064–1071, 2010. View at Publisher · View at Google Scholar · View at Scopus
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- D. D. Schoepp, R. A. Wright, L. R. Levine, B. Gaydos, and W. Z. Potter, "LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress," Stress, vol. 6, no. 3, pp. 189–197, 2003. View at Publisher · View at Google Scholar · View at Scopus
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Purdue University to cut 33 jobs in Printing Services amid two-year tuition freeze
All departments asked to cut back
WEST LAFAYETTE, Ind. - Purdue University is cutting 33 positions after President Mitch Daniels called on all departments to trim costs amid a two-year tuition freeze.
The cuts will affect the school's Printing Services, reducing the number of employees from 48 to 15.
Purdue officials cited fewer printing projects and revenue loss for the layoffs.
The 33 employees' last day will be May 3.
Purdue's tuition freeze means the cost of basic in-state tuition will remain at about $10,000 until the end of the 2014-2015 school year, marking the first year without an increase since 1976.
Daniels has said $40 million will need to be cut from Purdue's budget to accommodate the freeze.

subset: commoncrawl


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Digital Outback Photo reviews Autopano Pro
Tuesday 29 July 2008
Online magazine Digital Outback Photo began a review of Autopano Pro. The magazine intends to follow closely the evolution of Autopano Pro and will continue its review in diary form.
Last time that Uwe Steinmueller, editor of Digital Outback Photo, used image stitching software was more than 3 years ago. After having received recommandations for Autopano Pro, he decided to put the program to the test.
What he expected from an automatic image stitching program is:
* Automatic and excellent alignment
* Color blending to produce smooth color transitions
* Automatic lens corrections
* Good projections
You can read the entire review on its dedicated web page.
The editor concludes by explaining his interest of using Autopano Pro for his future projects, and qualifies Autopano Pro as "a real 'auto'pano tool", "easy and fun to use".
Read the entire review
Visit Digital Ouback Photo
Tags: Autopano, press articles
You can leave a response, or trackback from your own site.


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I think when debating people, this has and will come up so although not a new discussion here goes...
I've often heard people say, atheism means a lack of a belief in god/gods which is a disbelief in god/gods which is the same thing as the belief that god/gods do not exist. Yet atheists say atheism is not a belief at all, "we do not believe in anything". Is this all just semantics? Is this worth talking about yet again? Do people get confused by this?
John Wilkins also wrote a lot about this at EvolvingThoughts.
http://evolvingthoughts.net/2011/07/atheism-agnosticism-and-theism-... is the last of those posts, with links to the previous ones. Worth reading.
The absence of belief in gods is not the same thing as a belief in the absence of gods. My daughter was an atheist until she went to school because she had no belief in gods. She did not believe that gods did not exist because she didn't know what gods were and I think this is the crux of the issue. Saying that atheism is a belief that gods don't exist makes gods a subject to disbelieve in. Saying that atheism is the lack of belief in gods makes the belief the subject .Belief is the acceptance of things without evidence. In this way the tone changes. It is not we who are having a belief in relation to gods but theists.
This is an important distinction for atheists who (usually) claim that god is invented by man.It is semantics of course but also literal - all other animals are atheist but they do not believe that gods don't exist. They have no belief in gods existing because they have not ever seen one. The default state of humans is also not to believe in things we can't see and it is theists who have invented gods to explain things they did not understand and make us distinct from the other animals. Therefore many atheists, including me, feel it is important to stress that it is theists who have the belief in relations to gods.
I think the question comes down to how one would act when it came to a situation where it made a difference whether you believed in the existence of deities or simply doubted their existence.
If a vision appeared to you in a fashion that was plainly either miraculous or illusory and it said "I am Yahweh. Believe in me or spend eternity in a lake of fire," how would you respond? You wouldn't be able to get away with merely having no opinion.
To me, it seems if you're an atheist, you'd assume it's an illusion based on your active disbelief in such stuff.
if you're an agnostic, you'd be confused and unable to form a firm opinion, but you might, in Pascal's Wager fashion, decide to commit to belief.
If you're a believer, You believe it already anyway.
Although to a tribe of people living in complete isolation and never having invented (or long forgotten about) the idea of gods may be infulenced towards theism by a travelling missionary. their lack of a belief does not make them bulletproof to conversion. I think that your example of an atheist is leaning to much towards a skeptic to be a fair example.
The problem is that both people who simply "lack"any kind of theistic belief system and those (like me) who are quite certain that nothing like a god could possibly exist often use the same word - "atheist" - to describe themselves. Personally, I make my position clear by calling myself an "antitheist," which, by implication, renders the term, "atheism" as denoting nothing more than an absence of belief rather than an affirmative denial (THERE IS NO GOD, PERIOD!) of any god's existence. I agree with "unseen:" one is either an agnostic or an antitheist; "atheist" is too confounded ambiguous to be definitively useful.
The problem of the "lackers" is that they are then confused with the group that simply doesn't think about the existence of God or deities. A lot of the objectionable ambiguity in their position comes from that.
Perhaps a new term needs to be coined to clear up any miscomunication.
There is an issue of context. If we're talking religious demography, then I think a broad, all-inclusive definition denoting all those that are not theists is fine. In a similar sense, if we're talking about cultural identity, I think it's fine to use 'atheism' as a means of contrasting an individual or group from theists and theism.
When it comes to philosophy, 'lack of belief', as a standalone, doesn't really work. It's essentialy not taking a position. In this context, I'd say a certain level of deliberation and consideration is required.
Yeah. "Poop or get off the pot," in other words. Take a real stand.
True, active disbelief makes one Atheist. But active disbelief is still a lack of belief. Lack of belief is simply the most encompassing definition. The lack of belief is the root of makes one Atheist, but one can be disbelieve to different degrees.
Knows there's a god
Thinks there's a god
Lacks belief in gods (passive Atheism)
Thinks there are no gods
Knows there's no gods
One thing that is important to consider is the common misuse of Agnostic to be a middle-ground regarding belief or, that they simply don't know there's a God. This comes from the theistic statement that Atheism is the affirmative claim that god doesn't exist. Such a person would be an Atheist, but the absolute claim of nonexistence is not required to be an Atheist. So in reality, the Agnostic claim of 'I don't know there's no god' is actually correct until they say that they aren't an Atheist though. The fact of the matter is that they are both. They may have bought into the false definitions some believers throw about, or they may be simply using the terminology that the believer will understand. Still, we must remember that Atheism concerns belief, whereas Agnosticism concerns knowledge. So in this regard, Agnostic is very reasonably. But it says nothing of what I believe. That is why I would be best classified as an Agnostic Atheist. I don't know there is no god, but I also don't believe in gods.
Are you saying it's possible to know something but not believe it?
I don't think it's possible, most of the time anyway, to keep knowledge and belief as separate as you make it sound. In order to believe something, you have to feel you know it, don't you? And when you know something, it's virtually impossible not to believe it.
"I believe (because I think I know) that the mustard is behind the milk in my refrigerator."
"I know I paid more than $500 for my bicycle, so of course I believe it."
BTW, I'm the other guy here who calls himself and atheistic agnostic (or vice versa).
Are you saying it's possible to know something but not believe it?
No, not at all. It's obvious that if you know something, that you also believe it to be true. But the inverse is the part that's not necessarily true. You can believe something without knowing for 100% fact that it is so. Like I don't believe in a god. Although I feel that the chances of a god are slim, I must admit that I am not omniscient and can't claim absolute certainty that no variety of god exists. I can still believe there are none based off the staggering lack of reason to believe the claims are so. But the honest thing is to admit that I don't know with 100% certainty. I can be 99% sure, but that still leaves room for the possibility that I'm wrong. I agree with the rest though. :)
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Archive for July 9th, 2010
South Florida Spa Lovers Celebrate Miami Spa Month
While the mercury rises in Miami, the prices at South Florida's spas are dropping—again. From now until August 31st, relaxation seekers can enjoy $99 treatments (normally valued at $199 or more) at 36 different spas thanks to the third annual Miami Spa Month. These healthy havens are offering everything from classic massages to mango manicures. And, if the specially priced services do not pique the interest of spa-goers, some spots, such as Spa at Icon Brickell at the Viceroy, are offering 15% off services during the promotion period. This year, eight new spas are participating in the promotion, including:
•Bliss Spa, W South Beach
•Elemis Spa at Village of Merrick Park
•Exhale Spa at the EPIC Hotel
•RockResorts Spa at Tempo, Miami
For a complete list of participating spas, click here.
Skincare Guru Kate Somerville Launches New Book
Celebrity facialist Kate Somerville recently launched the book Complexion Perfection! (Hay House, 2010), a practical how-to guide to getting clear, radiant skin regardless of age, ethnicity, skin type, or concern. In the book, Somerville discusses simple strategies for achieving a clear complexion and helps readers understand cutting-edge treatments, technologies, and ingredients. My favorite part of the book is the section on how diet and lifestyle impact the skin. Did you know that almonds provide a very high degree of antioxidant protection, that blueberries fight inflammation at the cellular level, and that spinach helps protect against skin aging? Somerville also says that tomatoes are a rich source of lycopene, which can help reduce the risk of skin cancer, and even cooler is she says that eating a sauce made by simmering tomatoes in olive oil has been shown to protect the skin from sunburns, about the same amount as using a sunblock with an SPF of two or three. Interesting!


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The `Iao aquifer is Maui's main source of drinking water. Years of stream diversion by sugar and pineapple plantations have lowered ground water levels and increased salt water intrusion into wells. With the close of most of these plantations, millions of gallons of water that used to flow into the aquifer is taken from streams and communities only to be wasted, hoarded, or sold to the highest bidder, despite the fact that water in Hawai`i is a public trust resource.
In December 2005, Earthjustice -- on behalf of two Maui community groups, Hui o Na Wai `Eha and Maui Meadows Homeowners Association -- announced a groundbreaking resolution of litigation over ground water from the `Iao aquifer. In return for the groups and the state Office of Hawaiian Affairs withdrawing their legal challenges to the permit applications of the Maui County Department of Water Supply for ground water from the `Iao aquifer, Maui Mayor Alan Arakawa has committed to take the steps necessary to restore continuous base flows to streams overlying the aquifer that are currently diverted by former plantation interests.
This is an interim measure, as Earthjustice and the community groups continue to litigate in a related case to set instream flow standards that would provide minimum flows necessary to sustain public trust uses, such as ecological protection and Native Hawaiian taro farming.


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Within the writings of Miyamoto Musashi creator of The Niten Ichi Ryu,we always find the Hyoho Sanjukajo (35 notes) The Gorin-no-sho (Writings of the Five Elements) was written based on the Hyoho Sanjugokajo.
To study Dokkodo, and comprehend is meaning and quality, it is necessary to understand the awakening of the heart which is written at the beginning of Gorin-no-sho. According to writings in the Niten-Ki, Musashi had been taken ill and was receiving treatment at his residence which was within Chiba Jo (castle). On the 12th May in the year of Shoho (1645), seven days before he passed away he presented certain articles to close friends and followers. He asked these close friends to employ students who had no work to give them security. He then completed writing Dokkodo without fear or hesitation, with a clean, clear mind. In the historical document Niten-Ki there are nineteen phrases. Two more as written in Dokkodo are missing.
The last, Tsuneni Hyoho no michi o Hanarazu: Never part from the way of strategy, is contained the will which Musashi wanted to hand on to his followers before he passed on.
Mi o asaku omoi yo o fu kaku omou - Consider your superficiality and have profound thoughts for others.
Izure no michi nimo wakare wo kanashimazu - Never have a mind of adherence and attachment to all things. Jitatomoni Urami Kakotsu Kokoronashi - There should be no thought of bearing a grudge against each other. Rembo no michi omoi kokoro nashi - There is no time for thinking of romance. Mono goto ni suki konomu koto nashi - There should be no likes and dislikes. Shitaku ni oite nosomu kokoro nashi - Do no harbor a heart for keeping a residence. Mi hitotsuni bishoku wo konomazu - Likes and dislikes of sustenance. Dai mono naru furuki dogu shojisezu - Never let future generations have an attachment to weapons. Issho no aida yokoshin omoazu - Forget about human desire
Hyakutake-Watkin ©1992 |


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If you're looking for a cookie recipe that will look gorgeous on a tray and will WOW! your friends (for both beauty and taste), this is your cookie. I don't believe I have ever taken these cookies to a party and brought any home. I particularly love these because they all bake up on one tray in the oven.
And if you don't like raspberry preserves, I am sure these would also be wonderful with apricot preserves.
Some tips:
The dough does not spread out much on the tray. If you use a large cookie sheet you can get all eight of the rolls onto one sheet and be done with it.
I use a wooden spoon handle to make the indentation. Keep in mind that the indentation will rise a bit in baking. Don't be shy.
This does not use much jam at all – maybe 4 oz. at the most.
Raspberry Ribbon Cookies
1 cup softened butter
2 1/2 cups all-purpose flour
1/2 cup sugar
1 tsp. vanilla
1/4 tsp. salt
1 egg, slightly beaten
Raspberry jam, jelly or preserves
3/4 cup powdered sugar
1/4 tsp. almond extract
3 to 4 Tbsp. milk
In a mixing bowl beat the butter on medium/high for 30 seconds. Add about 1/2 the flour, along with the sugar, vanilla, egg and salt. Mix until thoroughly combined. Beat in the remaining flour, mixing until dough forms a ball. Gather dough into a ball and knead slightly on counter (mine is sometimes crumbly at first – work it with your hands until it forms a nice ball of dough).
Divide the dough into eight equal portions. On a lightly floured surface, roll each piece into a 9″ rope, being careful to keep an even thickness throughout (so they'll bake evenly). Place the ropes on an ungreased cookie sheet about 2″ apart.
With the side of your finger or the handle of a wooden spoon, press a long groove down the center of your ropes.
Bake at 375degrees F for 10 minutes. Remove tray from oven and spoon raspberry preserves/jam into the groove. Bake about 5 minutes more, or until the edges just start to brown.
Cool on cookie sheet for 5 minutes. While they're cooling, prepare glaze by stirring all ingredients in a bowl. You want the glaze to run off the spoon.
Using a large spatula, move the cookie logs onto a large cutting board (I use the back of a wooden one). Drizzle glaze over the HOT cookies. Cut logs into 1″ pieces. Transfer cookies to a cooling rack to cool.


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> Press Kit
Download the latest press materials about Wayne Scott and his latest release "This Weary Way" below. Preview images of the available documents are listed to the right. Requests for more information or booking inquiries can be made
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1. Click on the file you wish to download (file name will be highlighted).
2. Click the DOWNLOAD button.
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This Weary Way Album Cover
(photo: Jim McGuire)
Wayne Scott and Darrell Scott
(photo: Jim McGuire)
Wayne Scott
(photo: Jim McGuire)


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A place for positive thoughts, thank-you's, inspiration ... just pure happiness. In other words, the anti-vent.
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Simple lesson: there is no substitute for having good parents who bring you up with some decent values and a good education.
Unventers don't forget about how hard our Mothers had to work also.My Mother had 7 children,cooked 2 large meals a day,cleaned house,washed clothes in a old wringer washer which was very hard then hung them on the line.she made all the bread we ate.She kept the chickens and the milk cows up.She canned and dried fruit.And the thing I remember the most is her singing all the time.There was never such a loving lady as my Mother.
Some of us are the children and grandchildren of those hard working people. We listened to them, got ourselves educated and have successful careers. You choose the lessons you want to learn.
Don't forget to vote!
My Husband surprised me yesterday by making supper for me when I came home from work.What a nice surprise.
My Mom cooked from scratch also, but she did open canned and frozen foods - from hers and my Dad's garden. Wonderful food and great cook. I miss her still.
Chubby girls cuddle better.
Son is voting for the first time tomorrow.He has been reading everything he can about both sides.He told us last night that he has made up his mind on who will help the country the most.I am so proud of him.My child has become an adult.
I am thankful my family is accepting of the man I love. He is incredible and so are they.
Happiness is having been able to see my son and daughter grow up to be responsible adults.We have been so lucky.Thank you Jesus.
I know the Unventer that got the big freezer has got to be excited.When I first got mine I couldn't wait to fill it up.Just remember to date everything.
While you set your clocks back, don't forget to check the batteries in the smoke detectors and flashlights. And check your fire extinguishers to make sure they are up-to-date.
Handy Hardware in Tucker ROCKS!! They have all the hard to find stuff that nobody else wants to mess with. I love those guys.
There is an invisible expiraton date on our birth certificate but only God can read it. Aren't we glad!
I make banana pudding the old fashion way and it disappears in minutes. I should double the recipe. People don't like it when they get there too late for a bowl full. Am I mean or what?


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Letter to the Editor
Because this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text.
In the letter "Manic Psychosis and Auditory Hallucinations Following Traumatic Brain Injury in a 13-Year-Old Boy" by Mehdi Bennouna-Greene, MD, and colleagues in the April 2010 issue (J Clin Psychiatry 2010;71[4]:506–507), Dr Bennouna-Greene's name should have been hyphenated.
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February Real Estate Data: Condos Hit Hardest
The story of the day is still low supply driving big competition. Our agents are still seeing multiple offers, but the pace is going from fast to super-sonic, with more offers coming in on homes than even a month ago, and on different types of sales. It's never been uncommon to see banks price their… Read More


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Workers ready for businesses to hit Hays
By RANDY GONZALES
Aaron White, executive director of Ellis County Coalition for Economic Development, said there are workers available for businesses looking to find a home in Hays.
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By RANDY GONZALES
Aaron White, executive director of Ellis County Coalition for Economic Development, said there are workers available for businesses looking to find a home in Hays.
"We do have the available workforce; it's more of a hidden workforce," he told Ellis County commissioners during a presentation for funding at Monday's meeting.
"There are a large number of folks in the community, within our nine-county region, that have an interest in pursuing alternative careers, changing what they do," White said. "A large number of those folks are in the service and retail sector."
White is exploring ideas with North Central Kansas Technical College to help workers transition into new jobs. Potential workers would receive short-term, specific, general training courses.
"We kind of use the term boot camp training," for manufacturing jobs, White said.
"This is the type of thing to help those folks who don't have a strong mechanical background and would like to move into the production side of things, where the job opportunities are there," White said. "Give them the base set of skills they can take to an employer and move forward."
White said there are two small manufacturers looking to expand, and he is helping them secure facilities. One is a company that has outgrown its facilities in the downtown area, White said. The other company is looking to start a new business venture, White said.
Another company, Lion Chase, has decided to open a branch office in Hays, to market services and products for a Florida manufacturer.
"They have committed to moving to Hays and opening a branch of their facilities," White said. "It will be sales and marketing, primarily."
The manufacturer is related to power generation of clean energy.
"They view Kansas having a very significant market for some of the services and products that they offer," White said.
The company is looking for suitable space in Hays. Once that is attained, they will be up and running.
"They are getting pretty aggressive on what they think they can do in terms of hiring," White said. "They're looking at five to eight out of the gate, and if the sales and marketing in this region meet their expectations, they're talking about adding five employees every quarter for the next three years. Very progressive wages, good benefits."
"It's a little bit different type of work than anybody else in the region offers, so it's a nice diversification of our workforce base," White said.
White said he has received a few requests from companies looking for training and manufacturing centers.
"It's very early in the process, but the initial look at these look pretty positive," White said. "It's an interesting concept; it fills a need that the country is recognizing that there's a real gap in terms of skill trade."
White said a recent survey detailing what is wanted in Ellis County as far as retail choices has been helpful. He said two things can be done: approach existing businesses to see if they are interested in expanding what they offer, and if that doesn't work out, then approach retail chains about locating in Hays to fill the need.


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features at a glance
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Free Standing 3 Pole Design with Fiberglass
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Mesh Roof Vents increase ventilation and improve star gazing
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• Floor: 210D 110T Nylon Oxford, 2000mm Multi-pass Urethane coating
• Frame: Fiberglass
Rain fly, Fiberglass Poles, Pole Bag, Stake Bag, 7075 Aluminum Stakes,
Guy Ropes, Repair Swatches, Gear Loft, Mesh Storage Pocket, and Tent Bag
Additional Information
Manufacturer | Browning Camping |


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What CE Pro 100 integrators foresee as the biggest challenges in 2008
Jeff Galea comments in CE Pro magazine. Click for Slide Show ">CEPro Magazine
BTA receives CEPro Top 100 recognition!
We are a creative and award-winning System's Integrator that has been recognized by our peers as one of the Top 100 companies in the country for the second year in a row, by CEPro Magazine. We take a great deal of pride in what we do and who we do it for, using integrity, performance, […]


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Office of the Vice President
Steve Clark came to Oregon State University in July 2011 from serving as the president and publisher of the Portland Tribune and metro-area Community Newspapers Inc.
Clark spent the first dozen years of his career reporting, editing and publishing at newspapers in Gresham, Lake Oswego, West Linn, Pendleton and the Willamette Valley. He was later named publisher and chief operating officer of Community Newspapers, a Tigard-based company that included several Portland-area newspapers. He eventually became president and co-owner of the company with his wife, Randalyn.
In 2004, he was named president of the Oregon Publication Corp., Oregon's largest newspaper group, which includes the Portland Tribune and Sustainable Life magazine, as well as Community Newspaper's 16 weekly and monthly publications.
In addition to long-standing private sector and civic engagement in state economic development, transportation and land use matters, Clark is active with community engagement and volunteerism. In the past, he also served as a member of the College of Liberal Arts' Dean's Council at OSU, and has been a sponsor of the Austin Family Business Program Excellence Awards, the OSU College of Business Alumni and Business Partner Awards, and the OSU College of Engineering Oregon Stater Awards.
As Vice President, Clark oversees University Relations and Marketing, the university's primary communications branch, with marketing that supports student recruitment and raises awareness of OSU's impact, dissemination of news about teaching, research and faculty and student achievement, the development of a vibrant online presence and hosting university-wide events.
Clark has a bachelor's degree in journalism from Oregon State University.
For more information, contact:
Steve Clark
Vice President for University Relations and Marketing
634 Kerr Administration Building
Corvallis, Oregon 97331-2155
541.737.4875 phone
541.737.3033 fax
Alice Tucker, Executive Assistant
541.737.4875 | email@example.com
Annie Athon Heck, Associate Vice President
A former journalist and executive communications specialist, Annie Athon Heck joined Oregon State University in March 2013. She works with URM Vice President Steve Clark and others in the division to lead OSU's strategic communications and marketing efforts. In her role, Heck helps lead executive communications, marketing-communications for the Oregon State University Advantage, research enterprise communications, and university events.
Prior to arriving at OSU, Heck spent the past 13 years working at Hewlett-Packard, where she helped develop communication and messaging strategies for the company. She later led a global public relations program for the printing business's graphics segment and provided executive communications support for HP leaders.
From 1995-99, Heck was the communications director for the Corvallis School District 509J, where she also served as chief spokesperson. She was a political reporter for the Statesman-Journal newspaper in Salem from 1991-95, covering the state Legislature and governor's office.
Annie Athon Heck
Associate Vice President, University Relations and Marketing
Oregon State University
A416 Kerr Administration Bldg.
Corvallis, Oregon 97331
Phone: 541-737-0790


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