References of "Bettendorff, Lucien"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailThiamine and benfotiamine counteract stress-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice
Gorlova, Anna; Pavlov, Dmitrii; Anthony, Daniel C et al

in Neuropharmacology (2019)

The negative societal impacts associated with the increasing prevalence of violence and aggression is increasing, and, with this rise, is the need to understand the molecular and cellular changes that ... [more ▼]

The negative societal impacts associated with the increasing prevalence of violence and aggression is increasing, and, with this rise, is the need to understand the molecular and cellular changes that underpin ultrasound-induced aggressive behavior. In mice, stress-induced aggression is known to alter AMPA receptor subunit expression, plasticity markers, and oxidative stress within the brain. Here, we induced aggression in BALB/c mice using chronic ultrasound exposure and examined the impact of the psychoactive anti-oxidant compounds thiamine (vitamin B1), and its derivative benfotiamine, on AMPA receptor subunit expression, established plasticity markers, and oxidative stress. The administration of thiamine or benfotiamine (200 mg/kg/day) in drinking water decreased aggressive behavior following 3-weeks of ultrasound exposure and benfotiamine, reduced floating behavior in the swim test. The vehicle-treated ultrasound-exposed mice exhibited increases in protein carbonyl and total glutathione, altered AMPA receptor subunits expression, and decreased expression of plasticity markers. These ultrasound-induced effects were ameliorated by thiamine and benfotiamine treatment; in particular both antioxidants were able to reverse ultrasound-induced changes in GluA1 and GluA2 subunit expression, and, within the prefrontal cortex, significantly reversed the changes in protein carbonyl and polysialylated form of neural cell adhesion molecule (PSA-NCAM) expression levels. Benfotiamine was usually more efficacious than thiamine. Thus, the thiamine compounds were able to counteract ultrasound-induced aggression, which was accompanied by the normalization of markers that have been showed to be associated with ultrasound-induced aggression. These commonly used, orally-active compounds may have considerable potential for use in the control of aggression within the community. [less ▲]

Detailed reference viewed: 21 (3 ULiège)
Full Text
Peer Reviewed
See detailNeuroinflammation and aberrant hippocampal plasticity in a mouse model of emotional stress evoked by exposure to ultrasound of alternating frequencies
Pavlov, Dmitrii ULiege; Bettendorff, Lucien ULiege; Gorlova, Anna et al

in Progress in Neuro-Psychopharmacology and Biological Psychiatry (2019), 90

Emotional stress is a form of stress evoked by processing negative mental experience rather than an organic or physical disturbance and is a frequent cause of neuropsychiatric pathologies, including ... [more ▼]

Emotional stress is a form of stress evoked by processing negative mental experience rather than an organic or physical disturbance and is a frequent cause of neuropsychiatric pathologies, including depression. Susceptibility to emotional stress is commonly regarded as a human- specific trait that is challenging to model in other species. Recently, we showed that a 3-week-long exposure to ultrasound of unpredictable alternating frequencies within the ranges of 20-25kHz and 25-45kHz can induce depression-like characteristics in laboratory mice and rats. In an anti-depressant sensitive manner, exposure decreases sucrose preference, elevates behavioural despair, increases aggression, and alters serotonin-related gene expression. To further investigate this paradigm, we studied depression/distress-associated markers of neuroinflammation, neuroplasticity, oxidative stress and the activity of glycogen synthase kinase-3 (GSK-3) isoforms in the hippocampus of male mice. Stressed mice exhibited a decreased density of Ki67-positive and DCX-positive cells in the subgranular zone of hippocampus, and altered expression of brain- derived neurotrophic factor (BDNF), its receptor TrkB, and anti-apoptotic protein kinase B phosphorylated at serine 473 (AktpSer473). The mice also exhibited increased densities of Iba- 1-positive cells, increased oxidative stress, increased levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) in the hippocampus and plasma, and elevated activity of GSK-3 isoforms. Together, the results of our investigation have revealed that unpredictable alternating ultrasound evokes behavioural and molecular changes that are characteristic of the depressive syndrome and validates this new and simple method of modeling emotional stress in rodents. [less ▲]

Detailed reference viewed: 33 (4 ULiège)
Full Text
See detailLa souris, le patient, et le faux expert. Décryptage d'une mystification.
Bakker, Julie ULiege; Balthazart, Jacques ULiege; Baron, Frédéric ULiege et al

Article for general public (2018)

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les ... [more ▼]

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les contrôles qui y sont associés induisent de nombreuses contraintes pratiques, des charges administratives et des coûts financiers importants que les chercheurs seraient certainement heureux d'éviter s'il existait une alternative à l'expérimentation animale. [less ▲]

Detailed reference viewed: 213 (54 ULiège)
Full Text
Peer Reviewed
See detailMyoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness
Rademaker, Gilles ULiege; Hennequière, Vincent ULiege; Nokin, Marie-Julie ULiege et al

in Oncogene (2018)

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism ... [more ▼]

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism. [less ▲]

Detailed reference viewed: 107 (38 ULiège)
Full Text
Peer Reviewed
See detailThiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs
Whitfield, Kyly C.; Bourassa, Megan W.; Adamolekun, Bola et al

in Annals of the New York Academy of Sciences (2018), 1430

Thiamine is an essential micronutrient that plays a key role in energy metabolism. Many populations worldwide may be at risk of clinical or subclinical thiamine deficiencies, due to famine, reliance on ... [more ▼]

Thiamine is an essential micronutrient that plays a key role in energy metabolism. Many populations worldwide may be at risk of clinical or subclinical thiamine deficiencies, due to famine, reliance on staple crops with low thiamine content, or food preparation practices, such as milling grains and washing milled rice. Clinical manifestations of thiamine deficiency are variable; this, along with the lack of a readily accessible and widely agreed upon biomarker of thiamine status, complicates efforts to diagnose thiamine deficiency and assess its global prevalence. Strategies to identify regions at risk of thiamine deficiency through proxy measures, such as analysis of food balance sheet data and month-specific infant mortality rates, may be valuable for understanding the scope of thiamine deficiency. Urgent public health responses are warranted in high-risk regions, considering the contribution of thiamine defi- ciency to infant mortality and research suggesting that even subclinical thiamine deficiency in childhood may have lifelong neurodevelopmental consequences. Food fortification and maternal and/or infant thiamine supplementation have proven effective in raising thiamine status and reducing the incidence of infantile beriberi in regions where thiamine deficiency is prevalent, but trial data are limited. Efforts to determine culturally and environmentally appropriate food vehicles for thiamine fortification are ongoing. [less ▲]

Detailed reference viewed: 183 (7 ULiège)
Full Text
Peer Reviewed
See detailBenfotiamine Treatment Activates the Nrf2/ARE Pathway and is Neuroprotective in a Transgenic Mouse Model of Tauopathy
Tapias, Victor; Jainuddin, Shari; Ahuja, Manuj et al

in Human Molecular Genetics (2018), 27(16), 2874-2892

Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase ... [more ▼]

Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase occur in Alzheimer’s disease (AD). Thiamine deficiency exacerbates amyloid beta (Aβ) deposition, tau hyperphosphorylation, and oxidative stress. Benfotiamine (BFT) rescued cognitive deficits and reduced Aβ burden in APP/PS1 mice. In this study, we examined whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) in the P301S mouse model of tauopathy. Chronic dietary treatment with BFT increased lifespan, improved behavior, reduced glycated tau, decreased NFTs, and prevented death of motor neurons. BFT administration significantly ameliorated mitochondrial dysfunction and attenuated oxidative damage and inflammation. We found that BFT and its metabolites (but not thiamine) trigger the expression of Nrf2/ARE- dependent genes in mouse brain as well as in wild-type but not Nrf2-deficient fibroblasts. Active metabolites were more potent in activating the Nrf2 target genes than the parent molecule BFT. Docking studies showed that BFT and its metabolites (but not thiamine) bind to Keap1 with high affinity. These findings demonstrate that BFT activates the Nrf2/ARE pathway and is a promising therapeutic agent for the treatment of diseases with tau pathology, such as AD, frontotemporal dementia, and progressive supranuclear palsy. [less ▲]

Detailed reference viewed: 241 (4 ULiège)
Full Text
See detailL’expérimentation animale reste indispensable (OPINION)
Amorim, Christiani; Andris, Fabienne; Arckens, Lut et al

Article for general public (2017)

Trop fréquemment, l’expérimentation animale est présentée comme une pratique archaïque. Elle a bien changé. Et 100 % des patients traités le sont grâce aux concepts et techniques développés grâce à elle.

Detailed reference viewed: 102 (28 ULiège)
Full Text
See detailMyoferlin controls mitochondrial structure in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness
Rademaker, Gilles ULiege; Hennequière, Vincent ULiege; Brohée, Laura ULiege et al

Poster (2017, September 22)

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. Therapeutic options remain very limited and are still based on ... [more ▼]

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. Therapeutic options remain very limited and are still based on classical chemotherapies. Cell fraction can survive to the chemotherapy and is responsible for tumor relapse. It appears that these cells rely on OXPHOS for survival. Myoferlin, a membrane protein involved in cell fusion was recently shown by our laboratory to be overexpressed in pancreatic cancer. In the present study, we discovered that myoferlin was more expressed in cell lines undergoing oxidative phosphorylation (OXPHOS) than in glycolytic cell lines. In the former cell lines, we showed that myoferlin silencing reduced OXPHOS activity and forced cells to switch to glycolysis. The decrease in OXPHOS activity is associated with mitochondrial network disorganization. Dynamin-related protein (DRP)-1 phosphorylation led us to suggest mitochondrial fission, reducing cell proliferation, ATP production and inducing autophagy and ROS accumulation. To confirm the clinical importance of myoferlin in PDAC, we showed that low myoferlin expression was significantly correlated to high overall survival. Myoferlin staining of PDAC sections was negatively correlated with several 18FDG PET indices indicating that glycolytic lesions had less myoferlin. As the mitochondrial function is demonstrated to enhance the cell resistance to the treatment, the metabolic switch forced by myoferlin silencing could open up a new perspective in the development of therapeutic strategies. [less ▲]

Detailed reference viewed: 116 (42 ULiège)
Full Text
Peer Reviewed
See detailMetabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition
Hendrick, Elodie ULiege; Peixoto, Paul; Blomme, Arnaud et al

in Oncogene (2017)

Detailed reference viewed: 123 (14 ULiège)
Full Text
Peer Reviewed
See detailDibenzoylthiamine, a lipophilic thiamine precursor, protects against oxidative damage in neuroblastoma cells
Sambon, Margaux ULiege; Wins, Pierre; Bettendorff, Lucien ULiege

Poster (2017)

Recent evidence suggests that thiamine (vitamin B1) and some of its derivatives can exert prominent neuroprotective effects in the mammalian brain, particularly in mouse models of Alzheimer’s disease and ... [more ▼]

Recent evidence suggests that thiamine (vitamin B1) and some of its derivatives can exert prominent neuroprotective effects in the mammalian brain, particularly in mouse models of Alzheimer’s disease and tauopathies. As orally administered thiamine crosses intestinal and blood-brain barriers only slowly, precursors with higher bioavailability e.g. sulbutiamine, benfotiamine and dibenzoylthiamine, have been developed. We investigated the protective effects of thiamine and those precursors in neuroblastoma cells cultured in a medium containing minimal amounts of thiamine (10 nM), but sufficient to sustain normal growth. We induced oxidative stress by incubating the cells (24 h) in the presence of the neurotoxic agent paraquat (0.25 mM). This treatment reduced cell viability by 40%. When thiamine or the precursors were present simultaneously, we observed protective effects by the precursors while free thiamine was ineffective. Dibenzoylthiamine was most efficient, affording complete protection of cells at 10-20 µM. It also caused the highest increase in intracellular thiamine, suggesting that the protection from oxidative damage is linked to increased levels of free thiamine (rather than thiamine disphophate) in the neuroblastoma cells. The mechanism of this protective effect is presently under investigation. These results and others from our laboratory raise the possibility that dibenzoylthiamine might useful as a neuroprotective agent in neurodegenerative disease. [less ▲]

Detailed reference viewed: 45 (4 ULiège)
Full Text
Peer Reviewed
See detailBenfotiamine Treatment Activates Nrf2/ARE Pathway and is Neuroprotective in a Transgenic Mouse Model of Tauopathy
Tapias, Victor; Jainuddin, Shari; Ahuja, Manuj et al

Poster (2017)

Impaired glucose metabolism, decreased levels of thiamine (vitamin B1) and its phosphate esters, and downregulated activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha ... [more ▼]

Impaired glucose metabolism, decreased levels of thiamine (vitamin B1) and its phosphate esters, and downregulated activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase have been linked to Alzheimer’s disease (AD). Thiamine-deficient mice exhibit increased amyloid deposition, tau hyperphosphorylation, and oxidative damage1. Experimental evidence has shown that benfotiamine (BFT), a synthetic S-acyl derivative of thiamine, rescued cognitive deficits and reduced amyloid burden in APP/PS1 mice2. We investigated whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) ‒ which causes frontotemporal dementia in humans ‒ in a mouse model of tauopathy. Exposure to BFT resulted in increased lifespan, behavioral improvement, reduced and glycated tau and NFTs, and prevented neuronal death in P301S transgenic (TG) mice. In addition, BFT administration significantly ameliorated mitochondrial dysfunction, attenuated oxidative damage, and decreased the expression of several pro-inflammatory mediators, consistent with a possible activation of the Nrf2/ARE neuroprotective pathway. Accordingly, we found that BFT (but not thiamine) triggers the expression of Nrf2/ARE-dependent genes in wild-type (WT) but not in Nrf2-deficient fibroblasts. Our findings suggest that BFT is a promising therapeutic agent for the treatment of tauopathies. [less ▲]

Detailed reference viewed: 247 (4 ULiège)
Full Text
Peer Reviewed
See detailModified swim test as a model of enhanced contextual conditioning during depression: expression of GSK3 beta and effects of antidepressant treatment
Markova, N; Shevtsova, S; Vignisse, Julie et al

Poster (2017)

Impaired brain plasticity is a well-established pathophysiologic feature of depression, but little is known about an enhancement of depression-associated cognitive processing. We studied a novel paradigm ... [more ▼]

Impaired brain plasticity is a well-established pathophysiologic feature of depression, but little is known about an enhancement of depression-associated cognitive processing. We studied a novel paradigm that potentially models the augmented acquisition of adverse memories during the development of a depressive-like state in mice. We used a modification of the classic two-day protocol of a mouse Porsolt’s test with an additional session on Day 5 following the initial swim session. On the last day of testing, floating behavior, a parameter of helplessness, was increased in naïve mice that was accompanied by a reduction in the pGSK3b/GSK3b ratio and increased levels of brain GSK3b mRNA. The increase in GSK3b mRNA in prefrontal cortex during delayed testing session correlated with increases in floating behavior, which is not observed in the classic Porsolt’s paradigm. Replacement of the last swim session with exposure to the context of testing resulted in increased GSK3b mRNA level similar to the effect of swimming, while exclusion of the last swim session prevented these changes. The behavioral changes and the alterations in GSK3b gene and protein levels were prevented by 2-week treatment with a low dose of classical antidepressant tricyclic imipramine (7.5 mg/kg/day), or vitamin B1 (thiamine) (200 mg/kg/day), or with the highly bioavailable thiamine precursor benfotiamine (200 mg/kg/day). Our study also demonstrated, for the first time, the antidepressant-like properties of vitamin B1 and its pre-cursor, in a pre-clinical model of depression. Thus, the new forced swim test paradigm models the enhanced contextual conditioning of adverse memories so the individual animals with distinct susceptibility to this syndrome to be differentiated. [less ▲]

Detailed reference viewed: 56 (2 ULiège)
Full Text
Peer Reviewed
See detailThiamine and lipophilic thiamine precursors protect against oxidative damage in cultured neuroblastoma cells
Sambon, Margaux ULiege; Wins, Pierre; Bettendorff, Lucien ULiege

Poster (2017)

Recent evidence suggests that thiamine (vitamin B1) and some of its derivatives can exert prominent neuroprotective effects in the mammalian brain, particularly in mouse models of Alzheimer’s disease and ... [more ▼]

Recent evidence suggests that thiamine (vitamin B1) and some of its derivatives can exert prominent neuroprotective effects in the mammalian brain, particularly in mouse models of Alzheimer’s disease and tauopathies. As orally administered thiamine crosses intestinal and blood-brain barriers only slowly, precursors with higher bioavailability e.g. sulbutiamine, benfotiamine and dibenzoylthiamine, have been developed. We investigated the protective effects of thiamine and those precursors in neuroblastoma cells cultured in a medium containing minimal amounts of thiamine (10 nM). We induced oxidative stress by incubating the cells (24h) in the presence of the neurotoxic agent paraquat (0.25 mM). This treatment reduced cell viability by 40%. When thiamine or the precursors were present simultaneously, we observed protective effects by the precursors while free thiamine was ineffective.Dibenzoylthiamine was most efficient, affording complete protection of cells at 10-20 μM. It also caused the highest increase in intracellular thiamine, suggesting that the protection from oxidative damage is linked to increased levels of free thiamine (rather than thiamine diphosphate) in the neuroblastoma cells. These results and others from our laboratory raise the possibility that dibenzoylthiamine might useful as a neuroprotective agent in neurodegenerative disease. [less ▲]

Detailed reference viewed: 138 (6 ULiège)
Full Text
Peer Reviewed
See detailThiamine and benfotiamine improve cognition and ameliorate GSK-3β-associated stressinduced behaviours in mice
Markova, Nataliia; Bazhenova, Nataliya; Anthony, Daniel C et al

in Progress in Neuro-Psychopharmacology and Biological Psychiatry (2017), 75

Thiamine deficiency in the brain has been implicated in the development of dementia and symptoms of depression. Indirect evidence suggests that thiamine may contribute to these pathologies by controlling ... [more ▼]

Thiamine deficiency in the brain has been implicated in the development of dementia and symptoms of depression. Indirect evidence suggests that thiamine may contribute to these pathologies by controlling the activities of glycogen synthase kinase (GSK)-3β. While decreased GSK- 3β activity appears to impair memory, increased GSK-3β activity is associated with the distressed/depressed state. However, direct evidence for the effects of thiamine on GSK-3β function were not have not been reported. Here, we administered thiamine or, the more bioavailable precursor, benfotiamine at 200 mg/kg/day for 2 weeks to C57BL/6J mice, to determine whether treatment might affect behaviours that are known to be sensitive to GSK-3β activity and whether such administration impacts on GSK-3β expression within the brain. The mice were tested in models of contextual conditioning and extinction, a 5-day rat exposure stress test, and a modified swim test with repeated testing. Imipramine (7.5 mg/kg/day) was administered as a positive control for thiamine or benfotiamine. As for imipramine, both compounds inhibited the upregulation of GSK-3β induced by predator stress or repeated swimming, and reduced floating scores and the predator stress-induced behavioural changes in anxiety and exploration. Coincident, thiamine and benfotiamine improved learning and extinction of contextual fear, and the acquisition of the step-down avoidance task. Together, our data indicate that thiamine and benfotiamine have antidepressant/anti-stress effects in naïve animals that are associated with reduced GSK-3β expression. Importantly, the treatment also had pro-cognitive actions despite the impact on GSK-3β activity. [less ▲]

Detailed reference viewed: 47 (9 ULiège)
Full Text
Peer Reviewed
See detailElucidating the functions of brain GSK3α: possible synergy with GSK3β upregulation and reversal by antidepressant treatment in a mouse model of depressive-like behaviour
Pavlov, Dmitrii; Markova, Nataliia; Bettendorff, Lucien ULiege et al

in Behavioural Brain Research (2017), 335

positively correlated with floating behavior on the third test. A twoweek- long pretreatment regime with imipramine (7.5 mg/kg/day) or thiamine (200 mg/kg/day), which is known to have antidepressant ... [more ▼]

positively correlated with floating behavior on the third test. A twoweek- long pretreatment regime with imipramine (7.5 mg/kg/day) or thiamine (200 mg/kg/day), which is known to have antidepressant properties, reduced the GSK3β over-expression and decreased floating behavior on Day 5. GSK3α mRNA levels were measured in the hippocampus and prefrontal cortex on Days 1, 2 and 5. GSK3α expression was decreased in the prefrontal cortex on Day 2 and increased on Day 5. In this model, GSK3α mRNA changes were prevented by imipramine or thiamine treatment. There was a significant correlation between the expression of the two isoforms in the prefrontal cortex on Day 2 in untreated group. These results provide the first evidence for the potential involvement of GSK3α in depressive-like behaviours and as a target of anti-depressant therapy. Furthermore, the correlations suggest some cross-talk may exist between the two GSK3 isoforms. [less ▲]

Detailed reference viewed: 31 (4 ULiège)
Full Text
Peer Reviewed
See detailThiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels
Vignisse, Julie ULiege; Sambon, Margaux ULiege; Gorlova, Anna et al

in Molecular and Cellular Neuroscience (2017), 82

Thiamine is essential for normal brain function and its deficiency causes metabolic impairment, specific lesions, oxidative damage and reduced adult hippocampal neurogenesis (AHN). Thiamine precursors ... [more ▼]

Thiamine is essential for normal brain function and its deficiency causes metabolic impairment, specific lesions, oxidative damage and reduced adult hippocampal neurogenesis (AHN). Thiamine precursors with increased bioavailability, especially benfotiamine, exert neuroprotective effects not only for thiamine deficiency (TD), but also in mouse models of neurodegeneration. As it is known that AHN is impaired by stress in rodents, we exposed C57BL6/J mice to predator stress for 5 consecutive nights and studied the proliferation (number of Ki67-positive cells) and survival (number of BrdU-positive cells) of newborn immature neurons in the subgranular zone of the dentate gyrus. In stressed mice, the number of Ki67- and BrdU-positive cells was reduced compared to non-stressed animals. This reduction was prevented when the mice were treated (200 mg/kg/day in drinking water for 20 days) with thiamine or benfotiamine, that were recently found to prevent stress-induced behavioral changes and glycogen synthase kinase-3β (GSK-3β) upregulation in the CNS. Moreover, we show that thiamine and benfotiamine counteract stress-induced bodyweight loss and suppress stress-induced anxiety-like behavior. Both treatments induced a modest increase in the brain content of free thiamine while the level of thiamine diphosphate (ThDP) remained unchanged, suggesting that the beneficial effects observed are not linked to the role of this coenzyme in energy metabolism. Predator stress increased hippocampal protein carbonylation, an indicator of oxidative stress. This effect was antagonized by both thiamine and benfotiamine. Moreover, using cultured mouse neuroblastoma cells, we show that in particular benfotiamine protects against paraquat-induced oxidative stress. We therefore hypothesize that thiamine compounds may act by boosting anti-oxidant cellular defenses, by a mechanism that still remains to be unveiled. Our study demonstrates, for the first time, that thiamine and benfotiamine prevent stress-induced inhibition of hippocampal neurogenesis and accompanying physiological changes. The present data suggest that thiamine precursors with high bioavailability might be useful as a complementary therapy in several neuropsychiatric disorders. [less ▲]

Detailed reference viewed: 62 (10 ULiège)
See detailThiamine: Biological forms and function
Bettendorff, Lucien ULiege

Conference (2017)

Detailed reference viewed: 62 (3 ULiège)
Full Text
Peer Reviewed
See detailInhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolismdependent manner
Bunik, Victoria; Mkrtchyan, Garait; Grabarska, Aneta et al

in Oncotarget (2016), 7(26400), 26421

2-Oxoglutarate dehydrogenase (OGDH) of the tricarboxylic acid (TCA) cycle is often implied to be inactive in cancer, but this was not experimentally tested. We addressed the question through specific ... [more ▼]

2-Oxoglutarate dehydrogenase (OGDH) of the tricarboxylic acid (TCA) cycle is often implied to be inactive in cancer, but this was not experimentally tested. We addressed the question through specific inhibition of OGDH by succinyl phosphonate (SP). SP action on different cancer cells was investigated using indicators of cellular viability and reactive oxygen species (ROS), metabolic profiling and transcriptomics. Relative sensitivity of various cancer cells to SP changed with increasing SP exposure and could differ in the ATP- and NAD(P)H-based assays. Glioblastoma responses to SP revealed metabolic sub-types increasing or decreasing cellular ATP/NAD(P)H ratio under OGDH inhibition. Cancer cell homeostasis was perturbed also when viability indicators were SPresistant, e.g. in U87 and N2A cells. The transcriptomics database analysis showed that the SP-sensitive cells, such as A549 and T98G, exhibit the lowest expression of OGDH compared to other TCA cycle enzymes, associated with higher expression of affiliated pathways utilizing 2-oxoglutarate. Metabolic profiling confirmed the dependence of cellular SP reactivity on cell-specific expression of the pathways. Thus, oxidative decarboxylation of 2-oxoglutarate is significant for the interdependent homeostasis of NAD(P)H, ATP, ROS and key metabolites in various cancer cells. Assessment of cellspecific responses to OGDH inhibition is of diagnostic value for anticancer strategies. [less ▲]

Detailed reference viewed: 43 (10 ULiège)
Full Text
Peer Reviewed
See detailCellular thiamine status is coupled to function of mitochondrial 2-oxoglutarate dehydrogenase
Mkrtchyan, Garik; Graf, Anastasia; Bettendorff, Lucien ULiege et al

in Neurochemistry International (2016), 101

Decreased thiamine and reduced activity of thiamine diphosphate (ThDP)-dependent 2-oxoglutarate dehydrogenase (OGDH) cause neurodegeneration. We hypothesized on concerted cell-specific regulation of the ... [more ▼]

Decreased thiamine and reduced activity of thiamine diphosphate (ThDP)-dependent 2-oxoglutarate dehydrogenase (OGDH) cause neurodegeneration. We hypothesized on concerted cell-specific regulation of the thiamine metabolism and ThDP-dependent reactions. We identified a smaller thiamine pool, a lower expression of the mitochondrial ThDP transporter, and a higher expression of OGDH in rat astrocytes versus neuroblastoma N2A. According to the data, the astrocytic OGDH may be up-regulated by an increase in intracellular ThDP, while the neuroblastomal OGDH functions at full ThDP saturation. Indeed, in rat astrocytes and brain cortex, OGDH inhibition by succinyl phosphonate (SP) enlarged the pool of thiamine compounds. Increased ThDP level in response to the OGDH inhibition presumably up-regulated the enzyme to compensate for a decrease in reducing power which occurred in SP-treated astrocytes. Under the same SP treatment of N2A cells, their thiamine pool and reducing power were unchanged, although SP action was evident from accumulation of glutamate. The presented data indicate that functional interplay between OGDH, other proteins of the tricarbocylic acid cycle and proteins of thiamine metabolism is an important determinant of physiology-specific networks and their homeostatic mechanisms. [less ▲]

Detailed reference viewed: 32 (8 ULiège)
Full Text
Peer Reviewed
See detailMolecular mechanisms of the non-coenzyme action of thiamin in brain: biochemical, structural and pathway analysis.
Mkrtchyan, Garik; Aleshin, Vasily; Parkhomenko, Yulia et al

in Scientific Reports (2015), 5

Detailed reference viewed: 45 (6 ULiège)