Publications by authors named "Neil Upton"

50 Publications

Preclinical Neuropathic Pain Assessment; the Importance of Translatability and Bidirectional Research.

Front Pharmacol 2020 8;11:614990. Epub 2021 Feb 8.

School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom.

For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved.
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http://dx.doi.org/10.3389/fphar.2020.614990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897667PMC
February 2021

The Antidepressant-Like Effects of a Clinically Relevant Dose of Ketamine Are Accompanied by Biphasic Alterations in Working Memory in the Wistar Kyoto Rat Model of Depression.

Front Psychiatry 2020 20;11:599588. Epub 2021 Jan 20.

Transpharmation Ireland Ltd., Trinity College Institute of Neuroscience (TCIN), Trinity College Dublin, Dublin, Ireland.

Major depressive disorder (MDD) is the leading cause of disability worldwide. The majority of antidepressant drugs require several weeks or months of treatment to demonstrate efficacy and a subset of patients are resistant to such interventions. Ketamine demonstrates rapid and long-lasting antidepressant effects in treatment resistant patients; however, side effects may limit its widespread clinical utility. The pharmaceutical industry is engaged in developing novel rapid-acting antidepressant drugs and the establishment of clinically relevant assays are needed to advance this process. Wistar Kyoto (WKY) rats are a valuable model of many of the characteristics of MDD and their resistance to selective serotonin reuptake inhibitors (SSRIs) in several behavioral paradigms emulates treatment resistance in clinical populations. Here, we confirmed the depressive-like phenotype of WKY rats in comparison to Sprague Dawley rats, characterized by increased immobility in the forced swim test, decreased locomotor activity and entries to the centre in the open field test, anhedonia in the female urine sniffing test and working memory deficits in the delayed non-match to position task. Single subcutaneous administration of 5 mg/kg ketamine in WKY rats mirrored the plasma exposure produced by the antidepressant dose in the clinic and rescued depressive-like behaviors. The same dose induced transient side effects, including decreased locomotor activity and reduced positive affect-associated vocalizations. Furthermore, ketamine acutely impaired working memory but induced pro-cognitive effects at a later time point. These data confirm the WKY rat as a preclinical model of depression. Ketamine's efficacy in recovering this depressive-like phenotype while inducing transient dissociative-like effects supports this as a translational model suitable for investigating novel antidepressant drugs.
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http://dx.doi.org/10.3389/fpsyt.2020.599588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863985PMC
January 2021

Evaluation of Selective 5-HT Agonists in Acute Seizure Models.

ACS Chem Neurosci 2019 07 13;10(7):3284-3295. Epub 2019 May 13.

Intervivo Solutions Inc , Toronto , ON M5A 4K2 , Canada.

The 5-HT releaser/reuptake inhibitor fenfluramine has been recently reported to provide benefit as an adjunctive treatment for Dravet and Lennox-Gastaut syndromes, two types of severe childhood epilepsy. Despite its enhancement of 5-HT function, many effects of fenfluramine have been demonstrated to be dependent on 5-HT receptor activation, suggesting that 5-HT receptor activation may have an anticonvulsant property. The present study was designed to evaluate fenfluramine and 5-HT agonists of varying 5-HT agonist selectivity, the relatively nonselective mCPP and Ro 60-0175, and the selective 5-HT agonists lorcaserin and CP-809101 across a variety of acute seizure tests conducted in adult rats and mice, which have been instrumental in identifying the majority of clinically efficacious antiepileptic drugs. Tests included the maximal electroshock seizure (MES), MES threshold, and 6 Hz electrical convulsive seizure models and the chemoconvulsant pentylenetetrazole test. The effect of mCPP, lorcaserin, and CP-809101 against electrically evoked seizures in amygdala kindled rats was also investigated. Overall, at doses known to interact with 5-HTR, there was no clear class-related effect of these agonists in any test. The only notable antiseizure effect of fenfluramine was inhibition of MES-induced tonic seizures in the rat. The current preclinical studies using the classical acute seizure tests and an amygdala kindling model do not identify a reliable antiseizure effect of fenfluramine, an agent now used in the treatment of human epilepsies, including Dravet syndrome and Lennox-Gastaut syndrome. Given the nature of these epilepsies, early life and/or genetic models may have better construct validity and be more appropriate for further study.
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http://dx.doi.org/10.1021/acschemneuro.8b00739DOI Listing
July 2019

Neurokinin-1 receptor antagonist orvepitant is an effective inhibitor of itch-associated response in a Mongolian gerbil model of scratching behaviour.

Exp Dermatol 2014 Nov;23(11):858-60

NeRRe Therapeutics Ltd, Stevenage Bioscience Catalyst, Stevenage, UK.

Data suggest that substance P could play an important role in pruritus, and therefore, blockade of the neurokinin (NK)-1 receptor might be antipruritic. Thus, we explored in the Mongolian gerbil the effect on scratching behaviour, induced by intra-dermal injection of the NK-1 receptor-specific agonist GR73632, of oral administration of the NK-1 receptor antagonist orvepitant. Orvepitant at all doses tested (0.1-10 mg/kg p.o.) produced a profound inhibition of GR73632 (30 nmol i.d.) induced hindlimb scratching; the minimum effective dose of orvepitant in this model was identified as ≤0.1 mg/kg. The data generated supported the proposition that the antipruritic potential of orvepitant should be evaluated in clinical trials.
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http://dx.doi.org/10.1111/exd.12528DOI Listing
November 2014

Changes in resting connectivity with age: a simultaneous electroencephalogram and functional magnetic resonance imaging investigation.

Neurobiol Aging 2013 Sep 19;34(9):2194-207. Epub 2013 Apr 19.

Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.

Resting fluctuations in the blood oxygenation level-dependent signal have attracted considerable interest for their sensitivity to pathological brain processes. However, these analyses are susceptible to confound by nonneural physiological factors such as vasculature, breathing, and head movement which is a concern when investigating elderly or pathological groups. Here, we used simultaneous electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) (EEG/fMRI) to constrain the analysis of resting state networks (RSNs) and identify aging differences. Four of 26 RSNs showed fMRI and EEG/fMRI group differences; anterior default-mode network, left frontal-parietal network, bilateral middle frontal, and postcentral gyri. Seven RSNs showed only EEG/fMRI differences suggesting the combination of these 2 methods might be more sensitive to age-related neural changes than fMRI alone. Five RSNs showed only fMRI differences and might reflect nonneural group differences. Activity within some EEG/fMRI RSNs was better explained by neuropsychological measures (Mini Mental State Examination and Stroop) than age. These results support previous studies suggesting that age-related changes in specific RSNs are neural in origin, and show that changes in some RSNs relate better to elderly cognition than age.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.03.004DOI Listing
September 2013

The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H₃ receptor antagonist in patients with mild to moderate Alzheimer's disease: a preliminary investigation.

Curr Alzheimer Res 2013 Mar;10(3):240-51

GSK Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge Biomedical Campus, Cambridge CB2 2GG, UK.

Background: The histamine H3 receptor plays a critical role in the negative neuromodulation of neurotransmitters involved in cognitive function. H3 receptor antagonists/inverse agonists have been shown to exert pro-cognitive effects in pre-clinical models. GSK239512 is a potent and selective H₃ receptor antagonist developed for the treatment of cognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokinetics and pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimer's disease using ascending dose titration regimens.

Methods: The study was conducted in two parts. Part A was a single-blind, placebo run-in, flexible dose titration over 9 days in two cohorts, each consisting of two patients. Part B was a double-blind, randomised, placebo controlled, parallel group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients.

Results: Overall, the 5/10/20/40 μg and 10/20/40/80 μg regimens were well-tolerated. The regimen of 20/40/80/150 μg showed the poorest tolerability likely due to the higher starting dose. There were no clinically significant abnormalities in haematology, clinical chemistry, urinalysis parameters and cardiovascular parameters. GSK239512 had positive effects on tasks of attention and memory with effect sizes between 0.56 and 1.37.

Conclusions: GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer's disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10 μg and a maximum dose of 80 μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimer's disease. These findings await replication in a larger study.
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http://dx.doi.org/10.2174/1567205011310030003DOI Listing
March 2013

Age-related task sensitivity of frontal EEG entropy during encoding predicts retrieval.

Brain Topogr 2013 Oct 17;26(4):547-57. Epub 2013 Mar 17.

School of Psychology, NUI Galway, University Road, Galway, Ireland,

Age-related declines in memory may be due in part to changes in the complexity of neural activity in the aging brain. Electrophysiological entropy provides an accessible measure of the complexity of ongoing neural activity. In the current study, we calculated the permutation entropy of the electroencephalogram (EEG) during encoding of relevant (to be learned) and irrelevant (to be ignored) stimuli by younger adults, older adults, and older cognitively declined adults. EEG entropy was differentially sensitive to task requirements across groups, with younger and older controls exhibiting greater control of encoding-related activity than older declined participants. Task sensitivity of frontal EEG during encoding predicted later retrieval, in line with previous evidence that cognitive decline is associated with reduced ability to self-initiate encoding-related processes.
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http://dx.doi.org/10.1007/s10548-013-0278-xDOI Listing
October 2013

The age-related gliosis and accompanying deficit in spatial learning are unaffected by dimebon.

Neurochem Res 2013 Jun 26;38(6):1190-5. Epub 2012 Sep 26.

Trinity College Institute of Neuroscience and Physiology Department, Trinity College, Dublin, Ireland.

A non-selective antihistamine, dimebon, has recently emerged as a potential treatment for Alzheimer's disease and Huntington's disease. Dimebon exerts several effects in addition to its anti-histaminergic effect, and of particular interest is its ability to enhance cognitive function in several models. The mechanism underlying this is unknown though it has been suggested that it may be associated with its anti-cholinergic action. Dimebon has also been reported to be neuroprotective, perhaps as a result of its ability to stabilize mitochondria. We considered that these effects might impact on the well-described age-related impairment in spatial learning and therefore examined the effect of repeated administration of dimebon on performance of young and aged animals in the Morris water maze. Whereas a clear age-related deficit was observed, dimebon failed to exert any effect on performance. Similarly, dimebon exerted no effect on the age-related increase in hippocampal expression of several markers of microglial and astroglial activation. We conclude that, despite its cognitive enhancing effects in some models, dimebon failed to modulate the deficit in spatial learning in aged rats and the evidence suggests that the drug does not possess anti-inflammatory properties.
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http://dx.doi.org/10.1007/s11064-012-0884-0DOI Listing
June 2013

Age-related declines in delayed non-match-to-sample performance (DNMS) are reversed by the novel 5HT6 receptor antagonist SB742457.

Neuropharmacology 2012 Oct 2;63(5):890-7. Epub 2012 Jul 2.

Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.

Alterations in synaptic plasticity and neurocognitive function with age have been well documented in the literature. These changes are accompanied by modifications of neurotransmitter systems in the central nervous system (CNS). The serotonergic system in particular plays an important role in attention, alertness and cognition. Disturbances in serotonergic function have been implicated in differing neurological and neuropsychiatric disorders including depression, psychosis aggression and dementia. The serotonin receptor subtype 5HT6 is distributed within CNS regions relevant to learning and memory, including the striatum, cortex and hippocampus. We examined here the effects of acute and chronic administration of the 5HT6 receptor antagonist SB742457 on performance in a delayed non-matching-to-sample task (DNMS), which was used to identify neurocognitive differences between middle-aged (MA, 13 months) and young adult (YG, 3 months) rats. We found that MA rats have significantly lower performance in the DNMS task compared to YG rats. Acute administration of SB742457 (3 mg/kg/po) significantly improved performance of the MA rats. Chronic administration of SB742457 (3 mg/kg) reversed the age-related deficit of the MA to match their performance to that of YG rats. Furthermore, these improvements were observed for 1 week post-SB742457 treatment cessation. The acute and chronic effects of this treatment suggest that there is both an immediate effect on neurotransmitter action and potentially a longer-term modification of synaptic plasticity. Together these data indicate a role for modulation of the serotonergic system in the development of cognition-enhancing agents.
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http://dx.doi.org/10.1016/j.neuropharm.2012.06.034DOI Listing
October 2012

Electrophysiological entropy in younger adults, older controls and older cognitively declined adults.

Brain Res 2012 Mar 20;1445:1-10. Epub 2012 Jan 20.

School of Psychology, NUI, Galway, Ireland.

The current study examined electrophysiological entropy in younger adults, older adults, and older cognitively declined adults across four experimental conditions - eyes closed, eyes open, and during both encoding and recognition of words in a memory task. We hypothesised reduced entropy in older declined adults relative to both older controls and younger adults, with the largest group differences in entropy expected during the encoding and recognition phases of the experiment. We also hypothesised greater hemispheric asymmetry in younger adults compared with older controls and older declined adults. Results revealed significant increases in entropy from eyes closed to eyes open to task. Young adults showed higher entropy in the right relative to the left hemisphere in the temporal lobe and higher entropy in the left relative to the right hemisphere in the parietal lobe. Old cognitively declined adults showed no significant differences between right and left hemisphere entropy. There was a trend whereby older declined adults showed lower entropy than older controls in the frontal lobe, this difference being largest in the left hemisphere during the encoding phase of the experiment. Results indicate that measures of entropy are sensitive to information processing demands and that higher cognitive performance may not be a simple function of entropy level, but rather a combination of level and range, or differentiated range of entropy states across the brain.
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http://dx.doi.org/10.1016/j.brainres.2012.01.027DOI Listing
March 2012

A simultaneous ERP/fMRI investigation of the P300 aging effect.

Neurobiol Aging 2012 Oct 25;33(10):2448-61. Epub 2012 Jan 25.

Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.

One of the most reliable psychophysiological markers of aging is a linear decrease in the amplitude of the P300 potential, accompanied by a more frontal topographical orientation, but the precise neural origins of these differences have yet to be explored. We acquired simultaneous electroencephalogram (EEG)/functional magnetic resonance imaging (fMRI) recordings from 14 older and 15 younger adults who performed a 3-stimulus visual oddball task designed to elicit P3a and P3b components. As in previous reports, older adults had significantly reduced P3a/P3b amplitudes over parietal electrodes but larger amplitudes over frontal scalp with no between-group differences in accuracy or reaction time. Electroencephalogram/functional magnetic resonance imaging fusion revealed that the P3a age effects were driven by increased activation of left inferior frontal and cingulate cortex and decreased activation of inferior parietal cortex in the older group. P3b differences were driven by increased activation of left temporal regions, right hippocampus, and right dorsolateral prefrontal cortex in the older group. Our results support the proposal that the age-related P300 anterior shift arises from an increased reliance on prefrontal structures to support target and distractor processing.
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http://dx.doi.org/10.1016/j.neurobiolaging.2011.12.021DOI Listing
October 2012

Activation of α7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Aß-mediated inhibition of LTP in the rat hippocampus.

Eur J Pharmacol 2012 Feb 16;677(1-3):63-70. Epub 2011 Dec 16.

Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin 2, Ireland.

Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid ß-protein (Aß). The α7 nicotinic acetylcholine receptor agonist "compound A" ((R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl))thiophene-2-carboxamide) induced a rapid-onset persistent enhancement of synaptic transmission in the dentate gyrus in vitro. Consistent with a requirement for activation of α7 nicotinic acetylcholine receptors, the type II α7-selective positive allosteric modulator PheTQS ((3aR, 4S, 9bS)-4-(4-methylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) potentiated, and the antagonist methyllycaconitine (MLA) prevented the persistent enhancement. Systemic injection of the agonist also induced a similar MLA-sensitive persistent enhancement of synaptic transmission in the CA1 area in vivo. Remarkably, although compound A did not affect control long-term potentiation (LTP) in vitro, it prevented the inhibition of LTP by Aß1-42 and this effect was inhibited by MLA. These findings strongly indicate that activation of α7 nicotinic acetylcholine receptors is sufficient to persistently enhance hippocampal synaptic transmission and to overcome the inhibition of LTP by Aß.
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http://dx.doi.org/10.1016/j.ejphar.2011.12.008DOI Listing
February 2012

Effects of the selective 5-HT(7) receptor antagonist SB-269970 in animal models of psychosis and cognition.

Behav Brain Res 2012 Mar 16;228(1):211-8. Epub 2011 Dec 16.

Schizophrenia and Cognitive Disorders Discovery Performance Unit, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Ltd, New Frontiers Science Park, Harlow, Essex, CM19 5AW, UK.

The 5-hydroxytryptamine7 (5-HT7) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have attempted to evaluate the potential role of the 5-HT7 receptor in schizophrenia by utilising genetic or pharmacological tools but to date these have provided conflicting results. Here we investigate the effect of a selective 5-HT7 receptor antagonist, SB-269970, in in vivo psychosis and cognition models and relate efficacy to brain exposures of the compound. SB-269970 significantly attenuated amphetamine-induced rearing and circling in rats. A similar effect was observed in an N-methyl d-aspartic acid (NMDA) receptor antagonist driven psychosis model, where SB-269970 significantly reversed phencyclidine-induced hyperlocomotion, rearing and circling; although the effect was not as robust as with the 5-HT2a receptor antagonist positive control, MDL100,907. SB-269970 also attenuated a temporal deficit in novel object recognition (NOR), indicative of an improvement in recognition memory. Pharmacokinetic analysis of plasma and brain samples taken after behavioural testing confirmed that efficacy was achieved at doses and pre-treatment times where receptor occupancy was substantial. These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT7 receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia.
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http://dx.doi.org/10.1016/j.bbr.2011.12.009DOI Listing
March 2012

Behavioural and electrophysiological effects of visual paired associate context manipulations during encoding and recognition in younger adults, older adults and older cognitively declined adults.

Exp Brain Res 2012 Feb 6;216(4):621-33. Epub 2011 Dec 6.

Department of Psychology, NUI, Galway, Ireland.

The current study examined the EEG of young, old and old declined adults performing a visual paired associate task. In order to examine the effects of encoding context and stimulus repetition, target pairs were presented on either detailed or white backgrounds and were repeatedly presented during both early and late phases of encoding. Results indicated an increase in P300 amplitude in the right parietal cortex from early to late stages of encoding in older declined adults, whereas both younger adults and older controls showed a reduction in P300 amplitude in this same area from early to late phase encoding. In the right hemisphere, stimuli encoded with a white background had larger P300 amplitudes than stimuli presented with a detailed background; however, in the left hemisphere, in the later stages of encoding, stimuli presented with a detailed background had larger amplitudes than stimuli presented with a white background. Behaviourally, there was better memory for congruent stimuli reinstated with a detailed background, but this finding was for older controls only. During recognition, there was a general trend for congruent stimuli to elicit a larger amplitude response than incongruent stimuli, suggesting a distinct effect of context reinstatement on underlying patterns of physiological responding. However, behavioural data suggest that older declined adults showed no memory benefits associated with context reinstatement. When compared with older declined adults, younger adults had larger P100 amplitude responses to stimuli presented during recognition, and overall, younger adults had faster recognition reaction times than older control and older declined adults. Further analysis of repetition effects and context-based hemispheric asymmetry may prove informative in identifying declining memory performance in the elderly, potentially before it becomes manifested behaviourally.
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http://dx.doi.org/10.1007/s00221-011-2966-7DOI Listing
February 2012

Rosiglitazone enhances learning, place cell activity, and synaptic plasticity in middle-aged rats.

Neurobiol Aging 2012 Apr 4;33(4):835.e13-30. Epub 2011 Oct 4.

Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.

As an antidiabetic agent, rosiglitazone (ROSI) binds and activates peroxisome proliferator-activator receptor gamma (PPARγ), altering the expression of genes involved in glucose uptake and disposal, ultimately affecting glucose regulation. ROSI might therefore be a potential treatment to ameliorate age-related decline in cognitive function, particularly on an insulin-resistant background, where improvements in peripheral insulin sensitivity and central nervous system (CNS) glucose utilization may facilitate recovery of cognitive function. We therefore examined the amelioration potential of ROSI for neurocognitive deficits resulting from aging in an animal model. Behaviorally, acute and chronic ROSI treatments enhanced acquisition of learning in the water plus maze, a modified version of the Morris water maze task. In parallel, restoration of synaptic plasticity in the dentate gyrus of ROSI-treated middle-aged rats was evident after a single dose intake. Additionally, the spatial receptive fields of hippocampal CA1 place cells were significantly improved by chronic ROSI administration. ROSI treatment reversed basal plasma insulin abnormalities and increased hippocampal glucose transporter (GLUT)-3 expression in middle-aged rats. Taken together, these results suggest that ROSI modulates hippocampal circuitry effectively to promote an improvement in cognitive function, possibly via a glucose transporter-3 mechanism.
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http://dx.doi.org/10.1016/j.neurobiolaging.2011.08.013DOI Listing
April 2012

The neuroprotective effect of a specific P2X₇ receptor antagonist derives from its ability to inhibit assembly of the NLRP3 inflammasome in glial cells.

Brain Pathol 2012 May 27;22(3):295-306. Epub 2011 Oct 27.

Trinity College Institute for Neuroscience, Physiology Department, Trinity College, Dublin, Ireland.

Release of interleukin (IL)-1β from immunocompetent cells requires formation of the NACHT, LLR and PYD domains-containing protein 3 (NLRP3) inflammasome and caspase 1 activation. Adenosine 5'-triphosphate (ATP), acting on the P2X(7) receptor, is one factor that stimulates inflammasome assembly. We show that a novel specific P2X(7) receptor antagonist, GSK1370319A, inhibits ATP-induced increase in IL-1β release and caspase 1 activation in lipopolysaccharide (LPS)-primed mixed glia by blocking assembly of the inflammasome in a pannexin 1-dependent manner. GSK1370319A also inhibits ATP-induced subregion-specific neuronal loss in hippocampal organotypic slice cultures, which is dependent on its ability to prevent inflammasome assembly in glia. Significantly, GSK1370319A attenuates age-related deficits in long-term potentiation (LTP) and inhibits the accompanying age-related caspase 1 activity. We conclude that inhibiting P2X(7) receptor-activated NLRP3 inflammasome formation and the consequent IL-1β release from glia preserve neuronal viability and synaptic activity.
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http://dx.doi.org/10.1111/j.1750-3639.2011.00531.xDOI Listing
May 2012

Donepezil impairs memory in healthy older subjects: behavioural, EEG and simultaneous EEG/fMRI biomarkers.

PLoS One 2011 8;6(9):e24126. Epub 2011 Sep 8.

Trinity College Institute of Neuroscience and School of Psychology, Trinity College Dublin, Dublin, Ireland.

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024126PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169575PMC
March 2012

Electroencephalographic coherence, aging, and memory: distinct responses to background context and stimulus repetition in younger, older, and older declined groups.

Exp Brain Res 2011 Jul 17;212(2):241-55. Epub 2011 May 17.

School of Psychology, NUI, Galway, Ireland.

The current study examines the EEG coherence of young, old, and old declined adults performing a visual paired-associates task. In order to examine the effects of encoding context and stimulus repetition, target pairs were presented on either detailed or white backgrounds and were repeatedly presented during both early and late phases of encoding. Younger adults were found to have lower levels of frontal-temporal and temporal-parietal coherence, but higher levels of frontal-parietal coherence, particularly for the gamma frequency band. A number of differential coherence responses to background context and early- versus late-encoding phases were also observed across the groups, particularly for lower alpha and upper alpha frequencies. Coherence-performance maps were generated to further explore topographical differences in the relationship between coherence and performance across groups. Results revealed a more diffuse pattern of negative coherence-performance relations in older declined adults. Results are discussed in light of the literature on age-related cognitive decline.
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http://dx.doi.org/10.1007/s00221-011-2726-8DOI Listing
July 2011

Pittsburgh compound B (11C-PIB) and fluorodeoxyglucose (18 F-FDG) PET in patients with Alzheimer disease, mild cognitive impairment, and healthy controls.

J Geriatr Psychiatry Neurol 2010 Sep 29;23(3):185-98. Epub 2010 Apr 29.

Division of Geriatric Psychiatry, Columbia University, New York, USA.

Amyloid load in the brain using Pittsburgh compound B ((11)C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using fluorodeoxyglucose ((18)F-FDG) PET were evaluated in patients with mild Alzheimer disease (AD, n = 18), mild cognitive impairment (MCI, n = 24), and controls (CTR, n = 18). ( 11)C-PIB binding potential (BP(ND)) was higher in prefrontal cortex, cingulate, parietal cortex, and precuneus in AD compared to CTR or MCI and in prefrontal cortex for MCI compared to CTR. For (18)F-FDG, regional cerebral metabolic rate for glucose (rCMRGlu) was decreased in precuneus and parietal cortex in AD compared to CTR and MCI, with no MCI-CTR differences. For the AD-CTR comparison, precuneus BP(ND) area under the receiver operating characteristic (ROC) curve (AUC) was 0.938 and parietal cortex rCMRGlu AUC was 0.915; for the combination, AUC was 0.989. ( 11)C-PIB PET BP(ND) clearly distinguished diagnostic groups and combined with (18)F-FDG PET rCMRGlu, this effect was stronger. These PET techniques provide complementary information in strongly distinguishing diagnostic groups in cross-sectional comparisons that need testing in longitudinal studies.
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http://dx.doi.org/10.1177/0891988710363715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110668PMC
September 2010

Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP.

Neurobiol Aging 2012 Jan 10;33(1):162-75. Epub 2010 Apr 10.

Trinity College Institute of Neuroscience and Physiology Department, Trinity College, Dublin 2, Ireland.

Neuroinflammation is a significant and consistent feature of many neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). The greatest risk factor for neurodegenerative disorders is age and a proinflammatory phenotype in the aged brain is believed to contribute to these neurodegenerative conditions. In animal models, neuroinflammatory changes, characterized by increased microglial activation, have been associated with a loss of synaptic plasticity and here we show that treatment of aged rats with the PPARγ agonist, rosiglitazone, modulates the inflammatory changes and restores synaptic function. The evidence presented highlights an important role for astrocytes in inducing inflammatory changes and suggests that the age-related astrogliosis and astrocytosis is responsible for the increase in the proinflammatory cytokine, tumor necrosis factor alpha (TNF-α). Magnetic resonance (MR) imaging revealed an age-related increase in T1 relaxation time and, importantly, treatment of aged rats with rosiglitazone reversed the age-related increases in astrogliosis and astrocytosis, TNF-α concentration and T1 relaxation time. The evidence indicates that the site of action for rosiglitazone is endothelial cells, and suggests that its effect on astrocytes is secondary to its effect on endothelial cells.
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http://dx.doi.org/10.1016/j.neurobiolaging.2010.02.002DOI Listing
January 2012

H3 receptor antagonism enhances NCAM PSA-mediated plasticity and improves memory consolidation in odor discrimination and delayed match-to-position paradigms.

Neuropsychopharmacology 2009 Nov 5;34(12):2585-600. Epub 2009 Aug 5.

Berand Neuropharmacology, NovaUCD, Belfield Innovation Park, University College Dublin, Dublin, Ireland.

To further understand the procognitive actions of GSK189254, a histamine H(3) receptor antagonist, we determined its influence on the modulation of hippocampal neural cell adhesion molecule (NCAM) polysialylation (PSA) state, a necessary neuroplastic mechanism for learning and memory consolidation. A 4-day treatment with GSK189254 significantly increased basal expression of dentate polysialylated cells in rats with the maximal effect being observed at 0.03-0.3 mg/kg. At the optimal dose (0.3 mg/kg), GSK189254 enhanced water maze learning and the associated transient increase in NCAM-polysialylated cells. The increase in dentate polysialylated cell frequency induced by GSK189254 was not attributable to enhanced neurogenesis, although it did induce a small, but significant, increase in the survival of these newborn cells. GSK189254 (0.3 mg/kg) was without effect on polysialylated cell frequency in the entorhinal and perirhinal cortex, but significantly increased the diffuse PSA staining observed in the anterior, ventromedial, and dorsomedial aspects of the hypothalamus. Consistent with its ability to enhance the learning-associated, post-training increases in NCAM PSA state, GSK189254 (0.3 mg/kg) reversed the amnesia induced by scopolamine given in the 6-h post-training period after training in an odor discrimination paradigm. Moreover, GSK189254 significantly improved the performance accuracy of a delayed match-to-position paradigm, a task dependent on the prefrontal cortex and degree of cortical arousal, the latter may be related to enhanced NCAM PSA-associated plasticity in the hypothalamus. The procognitive actions of H3 antagonism combined with increased NCAM PSA expression may exert a disease-modifying action in conditions harboring fundamental deficits in NCAM-mediated neuroplasticity, such as schizophrenia and Alzheimer's disease.
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http://dx.doi.org/10.1038/npp.2009.89DOI Listing
November 2009

Protection against Aβ-mediated rapid disruption of synaptic plasticity and memory by memantine.

Neurobiol Aging 2011 Apr 14;32(4):614-23. Epub 2009 May 14.

Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.

Soluble amyloid-β protein (Aβ) may cause cognitive impairment in Alzheimer's disease in the absence of significant neurodegeneration. Here, the ability of the NMDA receptor (NMDAR) antagonist memantine to prevent synthetic Aβ-mediated rapid functional deficits in learned behavior and synaptic plasticity was assessed in the rat. In vitro, pretreatment with a clinically relevant, NMDAR blocking concentration of memantine partially inhibited the induction of long-term potentiation (LTP) in the dentate gyrus and prevented further inhibition caused by exposure to Aβ(1-42). Whereas systemic injection with memantine alone inhibited LTP in the CA1 area in vivo, a subthreshold dose partially abrogated the inhibition of LTP by intracerebroventricular soluble Aβ(1-42). Similarly, systemic treatment with memantine alone impaired performance of an operant learning task and a subthreshold dose prevented the Aβ(1-42)-mediated increase in perseveration errors. The acute protection afforded by memantine, albeit in a narrow dose range, against the rapid disruptive effects of soluble Aβ(1-42) on synaptic plasticity and learned behavior strongly implicate NMDAR-dependent reversible dysfunction of synaptic mechanisms in Aβ-mediated cognitive impairment.
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http://dx.doi.org/10.1016/j.neurobiolaging.2009.04.005DOI Listing
April 2011

Longitudinal regional brain volume changes quantified in normal aging and Alzheimer's APP x PS1 mice using MRI.

Brain Res 2009 May 9;1270:19-32. Epub 2009 Mar 9.

Department of Computing, Imperial College, London, UK.

In humans, mutations of amyloid precursor protein (APP) and presenilins (PS) 1 and 2 are associated with amyloid deposition, brain structural change and cognitive decline, like in Alzheimer's disease (AD). Mice expressing these proteins have illuminated neurodegenerative disease processes but, unlike in humans, quantitative imaging has been little used to systematically determine their effects, or those of normal aging, on brain structure in vivo. Accordingly, we investigated wildtype (WT) and TASTPM mice (expressing human APP(695(K595N, M596L)) x PS1(M146V)) longitudinally using MRI. Automated global and local image registration, allied to a standard digital atlas, provided pairwise segmentation of 13 brain regions. We found the mature mouse brain, unlike in humans, enlarges significantly from 6-14 months old (WT 3.8+/-1.7%, mean+/-SD, P<0.0001). Significant changes were also seen in other WT brain regions, providing an anatomical benchmark for comparing other mouse strains and models of brain disorder. In TASTPM, progressive amyloidosis and astrogliosis, detected immunohistochemically, reflected even larger whole brain changes (5.1+/-1.4%, P<0.0001, transgenexage interaction P=0.0311). Normalising regional volumes to whole brain measurements revealed significant, prolonged, WT-TASTPM volume differences, suggesting transgene effects establish at <6 months old of age in most regions. As in humans, gray matter-rich regions decline with age (e.g. thalamus, cerebral cortex and caudoputamen); ventricles and white matter (corpus callosum, corticospinal tract, fornix system) increase; in TASTPMs such trends often varied significantly from WT (especially hippocampus). The pervasive, age-related structural changes between WT and AD transgenic mice (and mouse and human) suggest subtle but fundamental species differences and AD transgene effects.
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http://dx.doi.org/10.1016/j.brainres.2009.02.045DOI Listing
May 2009

Circadian and dark-pulse activation of orexin/hypocretin neurons.

Mol Brain 2008 Dec 3;1:19. Epub 2008 Dec 3.

University of Manchester, UK.

Temporal control of brain and behavioral states emerges as a consequence of the interaction between circadian and homeostatic neural circuits. This interaction permits the daily rhythm of sleep and wake, regulated in parallel by circadian cues originating from the suprachiasmatic nuclei (SCN) and arousal-promoting signals arising from the orexin-containing neurons in the tuberal hypothalamus (TH). Intriguingly, the SCN circadian clock can be reset by arousal-promoting stimuli while activation of orexin/hypocretin neurons is believed to be under circadian control, suggesting the existence of a reciprocal relationship. Unfortunately, since orexin neurons are themselves activated by locomotor promoting cues, it is unclear how these two systems interact to regulate behavioral rhythms. Here mice were placed in conditions of constant light, which suppressed locomotor activity, but also revealed a highly pronounced circadian pattern in orexin neuronal activation. Significantly, activation of orexin neurons in the medial and lateral TH occurred prior to the onset of sustained wheel-running activity. Moreover, exposure to a 6 h dark pulse during the subjective day, a stimulus that promotes arousal and phase advances behavioral rhythms, activated neurons in the medial and lateral TH including those containing orexin. Concurrently, this stimulus suppressed SCN activity while activating cells in the median raphe. In contrast, dark pulse exposure during the subjective night did not reset SCN-controlled behavioral rhythms and caused a transient suppression of neuronal activation in the TH. Collectively these results demonstrate, for the first time, pronounced circadian control of orexin neuron activation and implicate recruitment of orexin cells in dark pulse resetting of the SCN circadian clock.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632999PMC
http://dx.doi.org/10.1186/1756-6606-1-19DOI Listing
December 2008

Analysis of serial magnetic resonance images of mouse brains using image registration.

Neuroimage 2009 Feb 29;44(3):692-700. Epub 2008 Oct 29.

Department of Computing, South Kensington Campus, Imperial College, London, UK. address:

The aim of this paper is to investigate techniques that can identify and quantify cross-sectional differences and longitudinal changes in vivo from magnetic resonance images of murine models of brain disease. Two different approaches have been compared. The first approach is a segmentation-based approach: Each subject at each time point is automatically segmented into a number of anatomical structures using atlas-based segmentation. This allows cross-sectional and longitudinal analyses of group differences on a structure-by-structure basis. The second approach is a deformation-based approach: Longitudinal changes are quantified by the registration of each subject's follow-up images to that subject's baseline image. In addition the baseline images can be registered to an atlas allowing voxel-wise analysis of cross-sectional differences between groups. Both approaches have been tested on two groups of mice: A transgenic model of Alzheimer's disease and a wild-type background strain, using serial imaging performed over the age range from 6-14 months. We show that both approaches are able to identify longitudinal and cross-sectional differences. However, atlas-based segmentation suffers from the inability to detect differences across populations and across time in regions which are much smaller than the anatomical regions. In contrast to this, the deformation-based approach can detect statistically significant differences in highly localized areas.
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http://dx.doi.org/10.1016/j.neuroimage.2008.10.016DOI Listing
February 2009

Voxel-based analysis of 11C-PIB scans for diagnosing Alzheimer's disease.

J Nucl Med 2008 Aug 16;49(8):1262-9. Epub 2008 Jul 16.

Department of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, New York, USA.

Unlabelled: The positron emission tomography (PET) radioligand N-methyl-11C-2-(4-methylaminophenyl)-6-hydroxybenzothiazole (also known as 11C-6-OH-BTA-1 or 11C-PIB) binds to amyloid-beta (Abeta), which accumulates pathologically in Alzheimer's disease (AD). Although 11C-PIB accumulation is greater in patients with AD than in healthy controls at a group level, the optimal method for discriminating between these 2 groups has, to our knowledge, not been established. We assessed the use of data-determined standardized voxels of interest (VOIs) to improve the classification capability of 11C-PIB scans on patients with AD.

Methods: A total of 16 controls and 14 AD age-matched patients were recruited. All subjects underwent a 11C-PIB scan and structural MRI. Binding potential (a measure of amyloid burden) was calculated for each voxel using the Logan graphical method with cerebellar gray matter as the reference region. Voxel maps were then partial-volume corrected and spatially normalized by MRI onto a standardized template. The subjects were divided into 2 cohorts. The first cohort (control, 12; AD, 9) was used for statistical parametric mapping analysis and delineation of data-based VOIs. These VOIs were tested in the second cohort (control, 4; AD, 5) of subjects.

Results: Statistical parametric mapping analysis revealed significant differences between control and AD groups. The VOI map determined from the first cohort resulted in complete separation between the control and the AD subjects in the second cohort (P < 0.02). Binding potential values based on this VOI were in the same range as other reported individual and mean cortical VOI results.

Conclusion: A standardized VOI template that is optimized for control or AD group discrimination provides excellent separation of control and AD subjects on the basis of 11C-PIB uptake. This VOI template can serve as a potential replacement for manual VOI delineation and can eventually be fully automated, facilitating potential use in a clinical setting. To facilitate independent analysis and validation with more and a broader variety of subjects, this VOI template and the software for processing will be made available through the Internet.
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http://dx.doi.org/10.2967/jnumed.107.049932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103049PMC
August 2008

5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease.

Neurotherapeutics 2008 Jul;5(3):458-69

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, United Kingdom.

Alzheimer's disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes, such as depression and psychosis. The neurochemical correlates of these clinical manifestations now appear to involve dysfunctions of multiple neurotransmitter pathways. Because of the extensive serotonergic denervation that has been observed in the AD brain and the important role played by serotonin (5-HT) in both cognition and behavioral control, this neurotransmitter system has become a focus of concerted research efforts to identify new treatments for AD. 5-HT exerts its diverse physiological and pharmacological effects through actions on multiple receptor subtypes. One of the newest members of this family is the 5-HT6 receptor, a subtype localized almost exclusively in the CNS, predominating in brain regions associated with cognition and behavior. With the subsequent development of selective 5-HT6 receptor antagonists, preclinical studies in rodents and primates have elucidated the function of this receptor subtype in more detail. It is increasingly clear that blockade of 5-HT6 receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms and also results in anxiolytic and antidepressant-like activity. These actions are largely underpinned by enhancements of cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission, together with learning-associated neuronal remodeling. A preliminary report that the cognitive enhancing properties of a 5-HT6 receptor antagonist (namely, SB-742457) extends into AD sufferers further highlights the therapeutic promise of this mechanistic approach.
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http://dx.doi.org/10.1016/j.nurt.2008.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084247PMC
July 2008

The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats.

Neuropharmacology 2008 Jun 1;54(8):1166-74. Epub 2008 Apr 1.

School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

While there is now substantial evidence that 5-HT(6) antagonism leads to significantly improved cognitive ability, the mechanism(s) and/or pathway(s) involved are poorly understood. We have evaluated the consequence of chronic administration of the 5-HT(6) receptor antagonists SB-271046 and SB-399885 on neural cell adhesion molecule polysialylation state (NCAM PSA), a neuroplastic mechanism necessary for memory consolidation. Quantitative analysis of NCAM PSA immunopositive neurons in the dentate gyrus of drug-treated animals revealed a dose-dependent increase in polysialylated cell frequency following treatment with both SB-271046 and SB-399885. These effects could not be attributed to increased neurogenesis, as no difference in the rate of bromodeoxyuridine incorporation was apparent between the control and drug-treated groups. A substantial increase in the frequency of polysialylated cells in layer II of the entorhinal and perirhinal cortices was also observed, brain regions not previously associated with neurogenesis. Chronic treatment with SB-271046 or SB-399885 also significantly increased the activation of dentate polysialylation that is specific to learning. This effect does not occur with other cognition-enhancing drugs, such as tacrine, and this action potentially differentiates 5-HT(6) receptor antagonism as an unique neuroplastic mechanism for cognitive processes which may slow or reverse age/neurodegenerative related memory deficits.
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http://dx.doi.org/10.1016/j.neuropharm.2008.03.012DOI Listing
June 2008

Symptomatic treatment of Alzheimer's disease: identification of biomarkers to aid translation from bench to bedside.

Biomark Med 2007 Jun;1(1):93-110

GlaxoSmithKline, Neurology and GI CEDD, New Frontiers Science Park North, Third Avenue, Harlow, Essex, CM19 5AW, UK.

In the absence of robust pharmacodynamic markers, the potential success of novel therapeutic agents for the symptomatic relief of Alzheimer's disease is largely unknown until the drugs enter relatively large studies, assessing clinical outcome over a 6-month period. In order to increase the efficiency of future clinical development there is, therefore, a need to identify pharmacodynamic markers of drug response, pharmacodynamic models that allow early prediction of efficacy and markers to aid the stratification of the patient population. Using literature available from cholinesterase inhibitors, memantine and Ginkgo biloba, this review focuses on the identification of potential pharmacodynamic markers/models and highlights the utility of these end points throughout the drug discovery process, from preclinical to clinical development.
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http://dx.doi.org/10.2217/17520363.1.1.93DOI Listing
June 2007

A beam-walking apparatus to assess behavioural impairments in MPTP-treated mice: pharmacological validation with R-(-)-deprenyl.

J Neurosci Methods 2007 Aug 6;164(1):43-9. Epub 2007 Apr 6.

Neurology & GI CEDD, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

A beam-walking apparatus has been evaluated for its ability to detect motor impairments in mice acutely treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, s.c., single or double administration). Mice subjected to MPTP lesioning showed deficits in motor performance on the beam-walking task, for up to 6 days post-MPTP administration, as compared to saline-treated controls. In addition, MPTP-treated mice were detected to have a marked depletion in striatal dopamine levels and a concomitant reduction in substantia nigra (SN) tyrosine hydroxylase (TH) immunoreactivity, at 7 days post-MPTP administration, indicative of dopaminergic neuronal loss. Pre-administration of the potent MAO-B inhibitor R-(-)-deprenyl at 3 or 10 mg/kg, 30 min, s.c, significantly inhibited the MPTP-induced reduction in SN TH-immunoreactivity, striatal dopamine depletions and impairments in mouse motor function. The data described in the present study provides further evidence that functional deficits following an acute MPTP dosing schedule in mice can be quantified and are related to nigro-striatal dopamine function.
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http://dx.doi.org/10.1016/j.jneumeth.2007.03.021DOI Listing
August 2007