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See detailConcomitant manipulation of NMDA- and AMPA-receptors to produce pro-cognitive drug effects
Vignisse, Julie ULg; Steinbusch, Harry W.M.; Grigoriev, Vladimir et al

in European Neuropsychopharmacology (2014), 24

Bifunctional drug therapy targeting distinct receptor signaling systems can generate increased efficacy at lower concentrations compared to monofunctional therapy. Non-competitive blockade of the NMDA ... [more ▼]

Bifunctional drug therapy targeting distinct receptor signaling systems can generate increased efficacy at lower concentrations compared to monofunctional therapy. Non-competitive blockade of the NMDA receptors or the potentiation of AMPA receptors is well documented to result in memory enhancement. Here, we compared the efficacy of the low-affinity NMDA receptor blocker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6J at 1 or 5 mg/kg, ip) with new derivatives of isothiourea (0.5-1 mg/kg, ip) that have bifunctional efficacy. Low-affinity NMDA blockade by these derivatives was achieved by introducing greater flexibility into the molecule, and AMPA receptor stimulation was produced by a sulfamide-containing derivative of isothiourea. Contextual learning was examined in a step-down avoidance task and extinction of contextual memory was studied in a fear-conditioning paradigm. Memantine enhanced contextual learning while QXX facilitated memory extinction; both drugs were effective at 5 mg/kg. The new derivative IPAC-5 elevated memory scores in both tasks at the dose 0.5 mg/Kg and exhibited the lowest IC50 values of NMDA receptor blockade and highest potency of AMPA receptor stimulation. Thus, among the new drugs tested, IPAC-5 plicated the properties of memantine and QXX in one administration with increased potency. Our data suggest that a concomitant manipulation of NMDA- and AMPA-receptors results in pro-cognitive effects and supports the concept bifunctional drug therapy as a promising strategy to replace monofunctional therapies with greater efficacy and improved compliance. [less ▲]

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See detailSimultaneous versus solitary pharmacological manipulation of NMDA- and AMPA- receptors: effects of new drugs on contextual learning and its extinction
Vignisse, Julie ULg; Steinbusch, Harry W.M.; Griegoriev, Vladimir et al

Poster (2012, July 17)

Both the attenuation of the NMDA-receptor mediated transmission via low affinity blockade mechanism, and the stimulation of AMPA receptor-mediated signaling were shown to result in beneficial ... [more ▼]

Both the attenuation of the NMDA-receptor mediated transmission via low affinity blockade mechanism, and the stimulation of AMPA receptor-mediated signaling were shown to result in beneficial neurobiological effects, such as an enhancement of memory and neurogenesis. We aimed to compare the effects of acute pharmacological manipulations of these mechanisms, exerted simultaneously or solely in mice, on learning of two mouse tasks with distinct predominant dependency on either glutamate receptor subtype. In a step-down avoidance task, memantine, low affinity NMDA receptor blocker (5 mg/kg), but not ampakine QQX (5 mg/kg) increased memory scores. In contrast, extinction of contextual fear conditioning was significantly enhanced by the latter, but not by the first drug. Among four new isothiourea derivates used at the doses 0.5-1 mg/kg, one compound that showed a maximal potency with respect to both glutamatergic mechanisms, as well as dimebon (1 mg/kg), had the most prominent memory enhancing effects. Thus, simultaneous low affinity blocade of the NMDA receptor and stimulation of AMPA-mediated transmission can result in eminent pro-cognitive activities. These data point to the importance of multi-target drug mechanism in the regulation of cognitive functions and suggest its potential for clinical implications. [less ▲]

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See detailAnhedonic-like traits and lack of affective deficits in 18-month-old C57BL/6 mice: Implications for modeling elderly depression.
Malatynska, Ewa; Steinbusch, Harry W. M.; Redkozubova, Olga et al

in Experimental Gerontology (2012), 47(8), 552-64

The prevalence of depression increases with aging. We hypothesized that like humans, old animals exhibit anhedonic-like behavior, along with signs of behavioral despair. In rodents, anhedonia, a reduced ... [more ▼]

The prevalence of depression increases with aging. We hypothesized that like humans, old animals exhibit anhedonic-like behavior, along with signs of behavioral despair. In rodents, anhedonia, a reduced sensitivity to reward, which is listed as a core feature of major depression in the DSM-IVR, can be measured by a decrease in intake of and preference for sweet solutions. Here, sucrose intake, forced swimming, immobility in the modified tail suspension test, novelty exploration, grooming, anxiety and locomotor activity were compared in naive 3- and 18-month-old male C57BL/6 mice. The absolute amounts and the ratio of consumed 1% sucrose solution to water intake was significantly smaller in 18-month-old mice than in 3-month-old mice. The consumption of 5%-sucrose solution requiring high levels of drinking effort, novelty exploration in two setups and grooming behavior in the splash test were reduced in older animals. Analysis of other behaviors suggested that the above-mentioned signs of anhedonic-like traits were unlikely to be attributable to the potential effect of aging on metabolic needs for water, taste perception, motor capabilities or the induction of essential anxiety and neophobia. A 4-week treatment with the antidepressant imipramine (7mg/kg/day) or dimebon, a compound with suggested neuroprotective proneurogenic properties (1mg/kg/day) restored sucrose intake and preference in 18-month-old mice. Meanwhile, young and old mice showed no differences in the parameters of behavioral despair evaluated in the forced swim and modified tail suspension tests. Thus, the behavioral profile of aged mice parallels that of humans with elderly depression, in whom the symptoms of hedonic deficits typically outweigh affective disturbances. The assessment of anhedonic-like traits with the sucrose preference test in 18-month-old mice will be useful in preclinical studies of elderly depression. [less ▲]

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See detailEffect of drug candidates for the treatment of Alzheimer's disorber on hippocampus-dependent learning, glutamate receptors and mitochondria
Vignisse, Julie ULg; Steinbusch, H.W.M; Bolkunov, A. et al

Conference (2011, November 12)

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See detailThiamin derivatives in the brain of a mouse model of Alzheimer's disease and in cultured Neuroblastoma cells treated with benfotiamine
Vignisse, Julie ULg; Liégeois, Jean-François ULg; Wins, Pierre et al

Poster (2011, July)

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder for which any disease-modifying treatment is available. It is estimated that approximately 36 million people suffer from this disease ... [more ▼]

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder for which any disease-modifying treatment is available. It is estimated that approximately 36 million people suffer from this disease and it comes with a high prize for the society. Recently, it has been shown that chronic administration of benfotiamine, a precursor of thiamin, in a mouse model of AD (APP/PS1 mice) significantly reduced key features of this disease namely memory impairment, β-amyloid accumulation and tau hyperphosphorylation. These beneficial effects are thought to be mediated by the PI3K/Akt/GSK3 signalling pathway (Pan et al., 2010). GSK3 is a kinase involved in the tau protein hyperphosphorylation in Alzheimer’s disease. It is however not clear how and which thiamine derivatives could interact with this kinase. Thiamine diphosphate is a well-known co-factor, in particular for mitochondrial pyruvate and oxo-glutarate dehydrogenases. However, other derivatives such as thiamine triphosphate and the newly discovered adenosine thiamine triphosphate are investigated in our laboratory. Therefore, we shall first try do determine whether benfotiamine (or one of its degradation products) or one of the above-mentioned thiamine derivatives are directly or indirectly involved in the regulation of the PI3K/Akt/GSK3 pathway in cultured neuroblastoma cells. For this purpose, neuroblastoma 2a cells will be grown in a thiamine-deficient medium containing benfotiamine, and thiamine derivatives (thiamine mono-, di- and triphosphate) will be measured by HPLC whereas Akt and GSK3 expression and phosphorylation levels will be assessed by immunoblotting. These experiments will give us new insights into the mechanism of action of thiamine derivatives, and according to the results obtained, we could then design new synthetic derivatives that would be more efficient than benfotiamine (very high doses were required in the animal experiments) in slowing down the neurodegenerative processes in Alzheimer’s disease. [less ▲]

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See detailDimebon Enhances Hippocampus-Dependent Learning in Mouse Models of Appetitive Y-Maze and Inhibitory Step-Down Memory Tasks in Mice
Vignisse, Julie ULg; Steinbusch, Harry W.M.; Bolkunov, Alexei et al

Poster (2011, February 23)

Dimebon, a compound recently proposed for a treatment of Alzheimer’s disorder, was suggested to have memory enhancing properties in pre-clinical and clinical studies. We investigated whether dimebon at ... [more ▼]

Dimebon, a compound recently proposed for a treatment of Alzheimer’s disorder, was suggested to have memory enhancing properties in pre-clinical and clinical studies. We investigated whether dimebon at doses acutely (0.1 mg/kg and 0.5 mg/kg) or repeatedly (0.1 mg/kg) administered to mice via i.p. injections, increases memory scores respectively in an appetitive and an inhibitory learning task. Acute treatment with dimebon at the dose 0.1 mg/kg did not affect learning scores in 3-month-old C57BL/6N. Acute treatment with higher dose of dimebon (0.5mg/kg) was found to enhance inhibitory learning in 3-month-old mice as shown in the step-down avoidance paradigm in C57BL/6N mice. In a model of appetitive learning, a spatial version of the Y-maze, repeated treatment with dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation. Repeated administration of dimebon also increased the duration of drinking behaviour during training/testing procedures although water consumption behaviour was not altered. Additional behavioural tests were carried out to investigate possible non-specific effects of dimebon on parameters of drinking, anxiety and exploration/locomotion. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice. [less ▲]

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See detailDimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice
Vignisse, Julie ULg; Steinbusch, Harry W.M.; Bolkunov, Alexei et al

Poster (2011, January 31)

Dimebon, a compound recently proposed for a treatment of Alzheimer’s disorder was suggested to have memory enhancing properties in pre-clinical and clinical studies. We investigated whether dimebon at ... [more ▼]

Dimebon, a compound recently proposed for a treatment of Alzheimer’s disorder was suggested to have memory enhancing properties in pre-clinical and clinical studies. We investigated whether dimebon at doses acutely (0.1 mg/kg and 0.5 mg/kg) or repeatedly (0.1 mg/kg) administered to mice via i.p. injections, increases memory scores respectively in an appetitive and an inhibitory learning task. Acute treatment with dimebon at the dose 0.1 mg/kg did not affect learning scores in either 3-month-old C57BL/6N or CD1 mice. Acute treatment with higher dose of dimebon (0.5mg/kg) was found to enhance inhibitory learning in 3- and 7-month-old mice as shown in the step-down avoidance paradigm in C57BL/6N mice. No effects on learning were seen in CD1 mice. In a model of appetitive learning, a spatial version of the Y-maze, repeated treatment with dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation. Repeated administration of dimebon also increased the duration of drinking behaviour during training/testing procedures although behaviours in others tests or water consumption were not altered. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice. [less ▲]

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See detailDimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice.
Vignisse, Julie ULg; Steinbusch, Harry W. M.; Bolkunov, Alexei et al

in Progress in Neuro-Psychopharmacology & Biological Psychiatry (2011), 35(2), 510-22

Pre-clinical and clinical studies on dimebon (dimebolin or latrepirdine) have demonstrated its use as a cognitive enhancer. Here, we show that dimebon administered to 3-month-old C57BL6N mice 15 min prior ... [more ▼]

Pre-clinical and clinical studies on dimebon (dimebolin or latrepirdine) have demonstrated its use as a cognitive enhancer. Here, we show that dimebon administered to 3-month-old C57BL6N mice 15 min prior to training in both appetitive and inhibitory learning tasks via repeated (0.1 mg/kg) and acute (0.5 mg/kg) i.p. injections, respectively, increases memory scores. Acute treatment with dimebon was found to enhance inhibitory learning, as also shown in the step-down avoidance paradigm in 7-month-old mice. Bolus administration of dimebon did not affect the animals' locomotion, exploration or anxiety-like behaviour, with the exception of exploratory behaviour in older mice in the novel cage test. In a model of appetitive learning, a spatial version of the Y-maze, dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation, and increased the duration of drinking behaviour during training/testing procedures. Repeated treatment with dimebon did not alter the behaviours in other tests or water consumption. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice. [less ▲]

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See detailFactors of Learning in Mouse Models of Memory and Evaluation of Effects of Dimebon
Vignisse, Julie ULg

Master's dissertation (2010)

1. Factors of learning in mouse models of memory The impact of several most relevant biological factors in contextual learning in mice was investigated in the first part of our study. It is of general ... [more ▼]

1. Factors of learning in mouse models of memory The impact of several most relevant biological factors in contextual learning in mice was investigated in the first part of our study. It is of general importance to estimate an impact of each of them in animals’ acquisition of various learning tasks during practical experimental work. First, factors of strain differences, aging and stress, investigated in our work can confound behavioural testing in memory paradigms. Second, they can be used as a basis of behavioural models of memory deficits and, thus, model pathological conditions in humans. Step-down avoidance task performed on three strains (namely C57BL/6N, CD1 and BALB/c) has clearly highlighted differences of abilities in learn contextual memory in these strains. The step-down avoidance task was also applied on C57BL/6N old of 3-months or 7-months; older mice displayed lower scores of memory then the young onces, thus, even mild aging impaired contextual learning in this strain. Third, we investigated learning of C57BL/6 mice subjected to chronic stress in a fear conditioning paradigm. Our study showed that the acquisition of this task was disrupted in stressed group, as reflected by decreased scores of freezing behavior. The assessment of investigated here factors of learning provides a possibility to validate animal models of memory and evaluate their sensitivity. 2. Evaluation of effects of dimebon Dimebon, a heterocyclic compounds previously adopted in clinic as antihistaminic, has recently revealed enhancing cognitive properties in pre-clinical and clinical studies The aim of the present study was to identify the most optimal dosing and adequate memory test(s), which would be sensitive to the memory enhancing effects of dimebon. Amongst the different studies realized, Dimebon revealed enhancement in memory in the step-down avoidance test, a one trial hippocampus-dependant task, at dose 0.5 mg/kg administered acutely and in the Y-Maze test, a multiple training paradigm at dose 0.1 mg/kg delivered chronically. In conclusion, our study supports therefore that the step-down avoidance and Y-maze paradigms are the most convenient assays allowing a rapid and reliable assessment of effects of of drugs with memory enhancing properties such as dimebon and dimebon-like. [less ▲]

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See detailAnomalous behaviour in the diffusion of polyethylene oxide through dialysis membrane
Vignisse, Julie ULg; Gustin, Audrey; Lespineux et al

Poster (2009, April 01)

Dialysis is a common technique adopted in biochemistry to purify biopharmaceutical drugs. This methodology is also of interest in macromolecular chemistry and pharmaceutical nanotechnology in order to ... [more ▼]

Dialysis is a common technique adopted in biochemistry to purify biopharmaceutical drugs. This methodology is also of interest in macromolecular chemistry and pharmaceutical nanotechnology in order to purify synthetic macromolecules and nanodrug carriers designed for drug delivery purposes. However, based on their original applications, the diffusion characteristic of the dialysis membrane is given in respect to the diffusion rate of globular proteins. So the diffusion capacity is function of molecular weight cut-off, i.e. corresponding to the maximum molecular weight of a globular macromolecule to be able to cross the membrane. The diffusion kinetics of synthetic macromolecules is expected to differ significantly from globular proteins due to at least the following differences : Specific relationship between hydrodynamic diameter and molecular weight, Flexibility Ionic density Solubility/miscibility/adsorption behaviour with the dialysis membrane Polymer chain entanglement above a critical concentration. In view to validate the application of this technique to purify synthetic macromolecules, we have compared the diffusion ability of neutral polyethyetylene oxide (PEO) standards or poly(dimethyl-aminoethyl-methacrylate) (PMADAM) to protein standards (human insulin and ovalbumin). [less ▲]

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