Eduard Bentea

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Oleg Yu Vorobyev

Siberian Federal University

Colin Simpson

University of NSW at Canberra

Srinivas Nammi

Western Sydney University

Serena Corr

University of Glasgow

Rafael Abargues

Universitat de València

shivani R pandya

Parul university

John Gamon

University of Alberta

F. Marinello

Università degli Studi di Padova

E. Savio

Università degli Studi di Padova

Patrick Grant

University of Oxford

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Papers by Eduard Bentea

Comparative analysis of antibodies to xCT (Slc7a11): Forewarned is forearmed

The Journal of comparative neurology, Jan 23, 2015

The cystine/glutamate antiporter or system Xc- exchanges cystine for glutamate, thereby supportin... more The cystine/glutamate antiporter or system Xc- exchanges cystine for glutamate, thereby supporting intracellular glutathione synthesis and nonvesicular glutamate release. The role of system Xc- in neurological disorders can be dual and remains a matter of debate. One important reason for the contradictory findings that have been reported to date is the use of nonspecific anti-xCT (the specific subunit of system Xc-) antibodies. Often studies rely on the predicted molecular weight of 55.5 kDa to identify xCT on Western blots. However, using brain extracts from xCT knockout (xCT(-/-) ) mice as negative controls, we show that xCT migrates as a 35-kDa protein. Misinterpretation of immunoblots leads to incorrect assessment of antibody specificity and thereby to erroneous data interpretation. Here we have verified the specificity of most commonly used commercial and some in-house-developed anti-xCT antibodies by comparing their immunoreactivity in brain tissue of xCT(+/+) and xCT(-/-) mic...

In-depth behavioral characterization of the corticosterone mouse model and the critical involvement of housing conditions

by Eduard Bentea and An De Prins

Physiology & Behavior, 2015

Depression and anxiety are disabling and highly prevalent psychiatric disorders. To better unders... more Depression and anxiety are disabling and highly prevalent psychiatric disorders. To better understand the neurobiological basis of mood and anxiety disorders, relevant animal models are needed. The corticosterone mouse model is frequently used to study depression. Chronic stress and accompanying glucocorticoid elevation causes pathological changes in the central nervous system, which are related to psychiatric symptoms. Exogenous administration of corticosterone is therefore often used to induce depressive-like behavior in mice and in some cases also features of anxiety-like behavior are shown. However, a thorough characterization of this model has never been conducted and housing conditions of the used subjects often differ between the implemented protocols. We chronically administered a subcutaneous corticosterone bolus injection to single- and group-housed mice, and we subsequently evaluated the face validity of this model by performing a battery of behavioral tests (forced swim test, mouse-tail suspension test, saccharin intake test, novelty-suppressed feeding test, elevated plus maze, light/dark paradigm and open field test). Our results show that corticosterone treatment has a substantial overall effect on depressive-like behavior. Increases in anxiety-like behavior on the other hand are mainly seen in single housed animals, independent of treatment. The current study therefore does not only show a detailed behavioral characterization of the corticosterone mouse model, but furthermore also elucidates the critical influence of housing conditions on the behavioral outcome in this model.

Alterations in the motor cortical and striatal glutamatergic system and D-serine levels in the bilateral 6-hydroxydopamine rat model for Parkinson’s disease

by Eduard Bentea and Anissa Arfani

Neurochemistry International, 2015

Parkinson&amp;amp;amp;amp;#39;s disease (PD) is hallmarked by progressive degeneration of the... more Parkinson&amp;amp;amp;amp;#39;s disease (PD) is hallmarked by progressive degeneration of the substantia nigra pars compacta (SNc) neurons and is associated with aberrant glutamatergic activity. However, studies on the glutamatergic system in the motor cortex and striatum, two motor loop-related areas, are lacking in the clinically relevant bilateral SNc 6-hydroxydopamine (6-OHDA) rat model, and therefore led to the rationale behind the present investigations. Using Western blotting, the expression levels of the glial glutamate transporters, GLT-1 and GLAST, as well as xCT, the specific subunit of system xc(-), and the vesicular glutamate transporters, VGLUT1 and 2 were investigated at two different time points (1 week and 2 weeks) post-lesion. In addition, the total content of glutamate was measured. Moreover, the total D-serine levels were, to the best of our knowledge, studied for the first time in these two PD-related areas in the bilateral 6-OHDA rat model. In the motor cortex, no significant changes were observed in the different glutamate transporter expression levels in the bilaterally-lesioned rats. In the striatum, GLAST expression was significantly decreased at both time points whereas VGLUT1 and 2 expressions were significantly decreased 2 weeks after bilateral 6-OHDA lesion. Interestingly, bilateral 6-OHDA SNc lesion resulted in an enhancement of the total D-serine content in both motor cortex and striatum at 1 week post-lesion suggesting its possible involvement in the pathophysiology of PD. In conclusion, this study demonstrates disturbed glutamate and D-serine regulation in the bilateral SNc-lesioned brain which could contribute to the behavioural impairments in PD.

$Research paper thumbnail of Validation of the 6 Hertz refractory seizure mouse model for intracerebroventricularly administered compounds$

Validation of the 6 Hertz refractory seizure mouse model for intracerebroventricularly administered compounds

Epilepsy Research, 2015

The six hertz (6 Hz) refractory seizure model is considered an indispensable chain of the Anticon... more The six hertz (6 Hz) refractory seizure model is considered an indispensable chain of the Anticonvulsant Screening Project. We here describe an adapted protocol using the intracerebroventricular (i.c.v.) delivery route, which will allow researchers to perform targetvalidation or proof-of-principle studies using promising compounds with unknown or limited blood-brain barrier permeability (e.g. neuropeptides and peptidomimetics) in this model. Seizures were induced by single application of a current intensity of 49 mA to i.c.v.-implanted NMRI mice using an ECT Unit 57800 Ugo Basile stimulator. By applying these key parameters, c-Fos immunohistochemistry revealed the recruitment of the dentate gyrus, ratifying this model as a valuable tool for testing i.c.v. administered compounds against therapy-resistant seizures. This finding was further strengthened, since i.c.v. administration of levetiracetam suppressed 6 Hz-evoked seizure severity but sodium phenytoin did not. We also propose to use &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;seizure duration&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; as an alternative, accurate parameter to express the results within this model.

Nigral proteasome inhibition in mice leads to motor and non-motor deficits and increased expression of Ser129 phosphorylated α-synuclein

by Eduard Bentea and Anissa Arfani

Frontiers in Behavioral Neuroscience, 2015

Parkinson's disease is a neurodegenerative disorder characterized by motor and non-motor disturba... more Parkinson's disease is a neurodegenerative disorder characterized by motor and non-motor disturbances. Various pathogenic pathways drive disease progression including oxidative stress, mitochondrial dysfunction, α-synuclein aggregation and impairment of protein degradation systems. Dysfunction of the ubiquitin-proteasome system in the substantia nigra of Parkinson's disease patients is believed to be one of the causes of protein aggregation and cell death associated with this disorder. Lactacystin, a potent inhibitor of the proteasome, was previously delivered to the nigrostriatal pathway of rodents to model nigrostriatal degeneration. Although lactacystin-treated animals develop parkinsonian motor impairment, it is currently unknown whether they also develop non-motor symptoms characteristic of this disorder. In order to further describe the proteasome inhibition model of Parkinson's disease, we characterized the unilateral lactacystin model, performed by stereotaxic injection of the toxin in the substantia nigra of mice. We studied the degree of neurodegeneration and the behavioral phenotype 1 and 3 weeks after lactacystin lesion both in terms of motor impairment, as well as non-motor symptoms. We report that unilateral administration of 3 µg lactacystin to the substantia nigra of mice leads to partial (∼40%) dopaminergic cell loss and concurrent striatal dopamine depletion, accompanied by increased expression of Ser129-phosphorylated α-synuclein. Behavioral characterization of the model revealed parkinsonian motor impairment, as well as signs of non-motor disturbances resembling early stage Parkinson's disease including sensitive and somatosensory deficits, anxiety-like behavior, and perseverative behavior. The consistent finding of good face validity, together with relevant construct validity, warrant a further evaluation of proteasome inhibition models of Parkinson's disease in pre-clinical research and validation of therapeutic targets.

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Lack of effect of Theiler’s murine encephalomyelitis virus infection on system xc−

Neuroscience Letters, 2015

Changes in the expression of xCT, the specific subunit of system xc(-) or the cystine/glutamate a... more Changes in the expression of xCT, the specific subunit of system xc(-) or the cystine/glutamate antiporter, have been associated with several neurological disorders and system xc(-) was recently proposed as a potential target for the development of new treatment strategies for multiple sclerosis (MS). In this study we used Theiler&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s murine encephalomyelitis virus (TMEV) infection, both in vitro and in vivo, as a model to further evaluate the involvement of system xc(-) in MS. Protein levels of xCT, as well as activity of system xc(-) were unaffected in RAW264.7 macrophages after infection with the demyelinating DA strain of TMEV. Also, protein expression of xCT remained stable in spinal cord and brain of FVB mice 1-2 and 6 weeks after intracranial injection of the DA strain of TMEV. These results demonstrate that TMEV infection of macrophages or FVB mice has no effect on system xc(-) and as such cannot be used as a model to study the involvement of system xc(-) in MS.

MPTP-induced parkinsonism in mice alters striatal and nigral xCT expression but is unaffected by the genetic loss of xCT

Neuroscience Letters, 2015

Nigral cell loss in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s d... more Nigral cell loss in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) is associated with disturbed glutathione (GSH) and glutamate levels, leading to oxidative stress and excitotoxicity, respectively. System xc- is a plasma membrane antiporter that couples cystine import (amino acid that can be further used for the synthesis of GSH) with glutamate export to the extracellular environment, and can thus affect both oxidative stress and glutamate excitotoxicity. In the current study, we evaluated the involvement of system xc- in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Our results indicate that the expression of xCT (the specific subunit of system xc-) undergoes region-specific changes in MPTP-treated mice, with increased expression in the striatum, and decreased expression in the substantia nigra. Furthermore, mice lacking xCT were equally sensitive to the neurotoxic effects of MPTP compared to wild-type (WT) mice, as they demonstrate similar decreases in striatal dopamine content, striatal tyrosine hydroxylase (TH) expression, nigral TH immunopositive neurons and forelimb grip strength, five weeks after commencing MPTP treatment. Altogether, our data indicate that progressive lesioning with MPTP induces striatal and nigral dysregulation of system xc-. However, loss of system xc- does not affect MPTP-induced nigral dopaminergic neurodegeneration and motor impairment in mice.

Altered vesicular glutamate transporter expression in human temporal lobe epilepsy with hippocampal sclerosis

Neuroscience Letters, 2015

Vesicular glutamate transporters (VGLUTs) are responsible for loading glutamate into synaptic ves... more Vesicular glutamate transporters (VGLUTs) are responsible for loading glutamate into synaptic vesicles. Altered VGLUT protein expression has been suggested to affect quantal size and glutamate release under both physiological and pathological conditions. In this study, we investigated mRNA and protein expression levels of the three VGLUT subtypes in hippocampal tissue of patients suffering from temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS), International League Against Epilepsy type1 (ILAE type1) compared to autopsy controls, using quantitative polymerase chain reaction and semi-quantitative western blotting. mRNA expression levels of the VGLUTs are unaffected in hippocampal epileptic tissue compared to autopsy controls. At the protein level, VGLUT1 expression remains unaltered, while VGLUT2 is significantly decreased and VGLUT3 protein is significantly increased in hippocampal biopsies from TLE patients compared to controls. Our findings at the protein level can be explained by previously described histopathological changes observed in HS. Although VGLUTs have been repeatedly investigated in distinct rodent epilepsy models, their expression levels were hitherto not fully unraveled in the most difficult-to-treat form of epilepsy: TLE with HS ILAE type1. We here, demonstrate for the first time that VGLUT2 protein expression is significantly decreased and VGLUT3 protein is significantly increased in the hippocampus of patients suffering from TLE with HS ILAE type1 compared to autopsy controls.

Oxidative Stress in Genetic Mouse Models of Parkinson’s Disease

Oxidative Medicine and Cellular Longevity, 2012

There is extensive evidence in Parkinson's disease of a link between oxidative stress and some of... more There is extensive evidence in Parkinson's disease of a link between oxidative stress and some of the monogenically inherited Parkinson's disease-associated genes. This paper focuses on the importance of this link and potential impact on neuronal function. Basic mechanisms of oxidative stress, the cellular antioxidant machinery, and the main sources of cellular oxidative stress are reviewed. Moreover, attention is given to the complex interaction between oxidative stress and other prominent pathogenic pathways in Parkinson's disease, such as mitochondrial dysfunction and neuroinflammation. Furthermore, an overview of the existing genetic mouse models of Parkinson's disease is given and the evidence of oxidative stress in these models highlighted. Taken into consideration the importance of ageing and environmental factors as a risk for developing Parkinson's disease, geneenvironment interactions in genetically engineered mouse models of Parkinson's disease are also discussed, highlighting the role of oxidative damage in the interplay between genetic makeup, environmental stress, and ageing in Parkinson's disease.

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Involvement of CRH Receptors in the Neuroprotective Action of R-Apomorphine in the Striatal 6-OHDA Rat Mode

Neuroscience & Medicine, 2013

Using Probabilistic Strategies to Formalize and Compare α-Synuclein Aggregation and Propagation under Different Scenarios

Lecture Notes in Computer Science, 2013

Absence of system xc- in mice decreases anxiety and depressive-like behavior without affecting sensorimotor function or spatial vision

Progress in neuro-psychopharmacology & biological psychiatry, Jan 23, 2015

There is considerable preclinical and clinical evidence indicating that abnormal changes in gluta... more There is considerable preclinical and clinical evidence indicating that abnormal changes in glutamatergic signaling underlie the development of mood disorders. Astrocytic glutamate dysfunction, in particular, has been recently linked with the pathogenesis and treatment of mood disorders, including anxiety and depression. System xc- is a glial cystine/glutamate antiporter that is responsible for nonvesicular glutamate release in various regions of the brain. Although system xc- is involved in glutamate signal transduction, its possible role in mediating anxiety or depressive-like behaviors is currently unknown. In the present study, we phenotyped adult and aged system xc- deficient mice in a battery of tests for anxiety and depressive-like behavior (open field, light/dark test, elevated plus maze, novelty suppressed feeding, forced swim test, tail suspension test). Concomitantly, we evaluated the sensorimotor function of system xc- deficient mice, using motor and sensorimotor based t...

Acute versus long-term effects of 6-hydroxydopamine on oxidative stress and dopamine depletion in the striatum of mice

Journal of Neuroscience Methods, 2011

Please cite this article in press as: Varcin M, et al. Acute versus long-term effects of 6-hydrox... more

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NMDA receptor antagonism potentiates the l-DOPA-induced extracellular dopamine release in the subthalamic nucleus of hemi-parkinson rats

by Najat Aourz, Anissa Arfani, and Eduard Bentea

Neuropharmacology, 2014

Long term treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is associated with several motor c... more Long term treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is associated with several motor complications. Clinical improvement of this treatment is therefore needed. Lesions or high frequency stimulation of the hyperactive subthalamic nucleus (STN) in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD), alleviate the motor symptoms and reduce dyskinesia, either directly and/or by allowing the reduction of the L-DOPA dose. N-methyl-D-aspartate (NMDA) receptor antagonists might have similar actions. However it remains elusive how the neurochemistry changes in the STN after a separate or combined administration of L-DOPA and a NMDA receptor antagonist. By means of in vivo microdialysis, the effect of L-DOPA and/or MK 801, on the extracellular dopamine (DA) and glutamate (GLU) levels was investigated for the first time in the STN of sham and 6-hydroxydopamine-lesioned rats. The L-DOPA-induced DA increase in the STN was significantly higher in DA-depleted rats compared to shams. MK 801 did not influence the L-DOPA-induced DA release in shams. However, MK 801 enhanced the L-DOPA-induced DA release in hemi-parkinson rats. Interestingly, the extracellular STN GLU levels remained unchanged after nigral degeneration. Furthermore, administration of MK 801 alone or combined with L-DOPA did not alter the STN GLU levels in both sham and DA-depleted rats. The present study does not support the hypothesis that DA-ergic degeneration influences the STN GLU levels neither that MK 801 alters the GLU levels in lesioned and non-lesioned rats. However, NMDA receptor antagonists could be used as a beneficial adjuvant treatment for PD by enhancing the therapeutic efficacy of l-DOPA at least in part in the STN.

Comparative analysis of antibodies to xCT (Slc7a11): Forewarned is forearmed

The Journal of comparative neurology, Jan 23, 2015

In-depth behavioral characterization of the corticosterone mouse model and the critical involvement of housing conditions

by Eduard Bentea and An De Prins

Physiology & Behavior, 2015

Alterations in the motor cortical and striatal glutamatergic system and D-serine levels in the bilateral 6-hydroxydopamine rat model for Parkinson’s disease

by Eduard Bentea and Anissa Arfani

Neurochemistry International, 2015

$Research paper thumbnail of Validation of the 6 Hertz refractory seizure mouse model for intracerebroventricularly administered compounds$

Validation of the 6 Hertz refractory seizure mouse model for intracerebroventricularly administered compounds

Epilepsy Research, 2015

Nigral proteasome inhibition in mice leads to motor and non-motor deficits and increased expression of Ser129 phosphorylated α-synuclein

by Eduard Bentea and Anissa Arfani

Frontiers in Behavioral Neuroscience, 2015

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Lack of effect of Theiler’s murine encephalomyelitis virus infection on system xc−

Neuroscience Letters, 2015

MPTP-induced parkinsonism in mice alters striatal and nigral xCT expression but is unaffected by the genetic loss of xCT

Neuroscience Letters, 2015

Altered vesicular glutamate transporter expression in human temporal lobe epilepsy with hippocampal sclerosis

Neuroscience Letters, 2015

Oxidative Stress in Genetic Mouse Models of Parkinson’s Disease

Oxidative Medicine and Cellular Longevity, 2012

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Involvement of CRH Receptors in the Neuroprotective Action of R-Apomorphine in the Striatal 6-OHDA Rat Mode

Neuroscience & Medicine, 2013

Using Probabilistic Strategies to Formalize and Compare α-Synuclein Aggregation and Propagation under Different Scenarios

Lecture Notes in Computer Science, 2013

Absence of system xc- in mice decreases anxiety and depressive-like behavior without affecting sensorimotor function or spatial vision

Progress in neuro-psychopharmacology & biological psychiatry, Jan 23, 2015

Acute versus long-term effects of 6-hydroxydopamine on oxidative stress and dopamine depletion in the striatum of mice

Journal of Neuroscience Methods, 2011

Please cite this article in press as: Varcin M, et al. Acute versus long-term effects of 6-hydrox... more

Download

NMDA receptor antagonism potentiates the l-DOPA-induced extracellular dopamine release in the subthalamic nucleus of hemi-parkinson rats

by Najat Aourz, Anissa Arfani, and Eduard Bentea

Neuropharmacology, 2014

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