Papers by Yvette Michotte
Seizure-european Journal of Epilepsy, 2011
The peptide angiotensin IV (Ang IV) influences seizure susceptibility in rat and mouse models. In... more The peptide angiotensin IV (Ang IV) influences seizure susceptibility in rat and mouse models. Indeed, Ang IV has been shown to protect rats from limbic seizures in the focal pilocarpine model. Moreover, both anticonvulsive and antiepileptogenic effects of Ang IV have been reported in the acute pentylenetetrazol (PTZ) and kindling model of generalized seizures in mice. It has been hypothesized
Intrastrain differences in seizure susceptibility, pharmacological response and basal neurochemistry of Wistar rats
Epilepsy Research, 2009
Reliable well-characterised animal models of seizures are necessary in order to better understand... more Reliable well-characterised animal models of seizures are necessary in order to better understand the underlying pathophysiological mechanisms as well as to screen potential anticonvulsant drugs. We currently use the focal pilocarpine model as an acute limbic seizure model. Due to breeding problems at the vendor, and apparent changes in pilocarpine-induced seizure susceptibility, we were forced to change breeding locations and vendors over a period of 2 years. Male Wistar rats were either purchased from two breeding locations of Charles River Laboratories (France and Germany), or obtained from Harlan Laboratories (The Netherlands). In the present retrospective study we evaluated the impact of these vendor changes on ketamine dosing to establish anaesthesia, on pilocarpine-induced seizure susceptibility, and on basal extracellular hippocampal noradrenaline, dopamine, serotonin, gamma-amino butyric acid, and glutamate levels of all pilocarpine-treated rats included in our studies. Significant differences were present in all of the parameters analyzed. This study clearly illustrates that intrastrain differences do exist from one vendor/breeding location to another, or even between rats from the same breeding location.
Neurobiology of Learning and Memory, 2009
The IRAP ligands Angiotensin IV (Ang IV) and LVV-haemorphin 7 (LVV-H7) enhance performance in a r... more The IRAP ligands Angiotensin IV (Ang IV) and LVV-haemorphin 7 (LVV-H7) enhance performance in a range of memory paradigms in normal rats and ameliorate memory deficits in rat models for amnesia. The mechanism by which these peptides facilitate memory remains to be elucidated. In recent in vitro experiments, we demonstrated that Ang IV and LVV-H7 potentiate activity-evoked glucose uptake into
Brain Research, 2007
Locally administered angiotensin IV causes a dose-dependent increase of the dopamine levels in th... more Locally administered angiotensin IV causes a dose-dependent increase of the dopamine levels in the striatum of the rat. The aminopeptidases insulin-regulated aminopeptidase (IRAP) and/or aminopeptidase N (AP-N) are proposed to be involved in this effect since both enzymes are inhibited by angiotensin IV. In agreement with this hypothesis we demonstrate that by using the AP-N selective inhibitor 7B, about 60%
Neuropharmacology, 2008
The neurobiological relationships between epilepsy and depression are receiving increased experim... more The neurobiological relationships between epilepsy and depression are receiving increased experimental attention. A key role for limbic monoamines in depression has been established and we recently showed the importance of hippocampal monoamines in limbic seizure control. We here studied whether anticonvulsant compounds are antidepressant and can elevate hippocampal dopamine (DA) or serotonin (5-HT) levels determined by in vivo microdialysis in
Journal of Neurochemistry, 2006
The anti-convulsant properties of angiotensin IV (Ang IV), an inhibitor of insulin-regulated amin... more The anti-convulsant properties of angiotensin IV (Ang IV), an inhibitor of insulin-regulated aminopeptidase (IRAP) and somatostatin-14, a substrate of IRAP, were evaluated in the acute pilocarpine rat seizure model. Simultaneously, the neurochemical changes in the hippocampus were monitored using in vivo microdialysis. Intracerebroventricularly (i.c.v.) administered Ang IV or somatostatin-14 caused a significant increase in the hippocampal extracellular dopamine and serotonin levels and protected rats against pilocarpine-induced seizures. These effects of Ang IV were both blocked by concomitant i.c.v. administration of the somatostatin receptor-2 antagonist cyanamid 154806. These results reveal a possible role for dopamine and serotonin in the anti-convulsant effect of Ang IV and somatostatin-14. Our study suggests that the ability of Ang IV to inhibit pilocarpine-induced convulsions is dependent on somatostatin receptor-2 activation, and is possibly mediated via the inhibition of IRAP resulting in an elevated concentration of somatostatin-14 in the brain. Fig. 3 Effect of the hippocampal perfusion of pilocarpine (10 mM) on the extracellular DA, 5-HT, Glu and GABA concentration in the hippocampus of the rat. Baseline levels are set to 100% (mean of six values)
Antimicrobial Agents and Chemotherapy, 2002
Fluoroquinolones are antibiotics with central excitatory side effects. These adverse effects pres... more Fluoroquinolones are antibiotics with central excitatory side effects. These adverse effects presumably result from inhibition of -aminobutyric acid (GABA) binding to GABAA receptors. This GABA antagonistic effect is greatly potentiated by the active metabolite of fenbufen, biphenylacetic acid (BPAA). Nevertheless, it remains questionable whether GABA receptor antagonism alone can explain the convulsant activity potentials of these antimicrobial agents. The present
An LC assay using a microcolumn coupled to a U-shaped optical cell for high sensitivity UV absorbance detection of oxcarbazepine and its major metabolite in microdialysates
Biomedical Chromatography, 1995
Narrow-bore liquid chromatographic assay for oxcarbazepine and its major metabolite in rat brain, liver and blood microdialysates
Journal of Chromatography B: Biomedical Sciences and Applications, 1994
An isocratic narrow-bore high-performance liquid chromatographic assay with UV detection is descr... more An isocratic narrow-bore high-performance liquid chromatographic assay with UV detection is described for the detection of oxcarbazepine and its major metabolite, 10,11-dihydro-10-hydroxycarbamazepine, using carbamazepine as the internal standard. This method is sufficiently sensitive to allow quantification of oxcarbazepine and its metabolite in rat brain, liver and blood microdialysates.
Naunyn-schmiedebergs Archives of Pharmacology, 1991
In the present study in vivo microdialysis sampling coupled to high-performance liquid chromatogr... more In the present study in vivo microdialysis sampling coupled to high-performance liquid chromatography with electrochemical detection, was used to study the pharmacokinetics of levodopa and 3-O-methyldopa in skeletal muscle in dog, after intravenous administration of levodopa. For comparison, the pharmacokinetic parameters of both compounds were simultaneously determined in plasma using blood collection. Muscle microdialysis samples and blood were continuously collected
Role of intrathecal IL1β on spinal glutamate and prostaglandin E2 releases in absence and presence of formalin-induced hind paw inflammation in the rat
Journal of Pain, 2005
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Intrathecal lidocaine elevates prostaglandin E2 levels in cerebrospinal fluid: a microdialysis study in freely-moving rats: A-717
European Journal of Anaesthesiology, 2005
In this study, we have investigated whether intrathecal (i.t.) lidocaine administration is accomp... more In this study, we have investigated whether intrathecal (i.t.) lidocaine administration is accompanied with changes of cerebrospinal fluid (CSF) prostaglandin E(2) (PGE(2)) levels. Rats were anaesthetized for i.t. implantation of a triple-lumen spinal loop dialysis catheter. CSF changes in PGE(2) after i.t. injection of saline, 400, or 1000 microg of lidocaine were measured. The impact of i.t. pretreatment with 5 microg MK801 (N-methyl-D-aspartate glutamate antagonist) or 10 microg SC76309A (COX-2 inhibitor) was also investigated. CSF dialysates for measurement of PGE(2) were collected for 4 h. During the whole procedure, motor and sensory blocks were evaluated. A separate group receiving i.t. lidocaine 400 microg (without dialysate sampling) was assessed for mechanical (Von Frey) and radiant heat pain. PGE(2) levels increased to 400% of baseline and remained elevated for 90-120 min after i.t. lidocaine at both doses. Pretreatment with SC76309A and MK801 attenuated this increase. A 40 min period of enhanced pain response was observed after Von Frey filament stimulation during and after sensory and motor block recovery. I.T. lidocaine (400 or 1000 microg) increases PGE(2) levels in the CSF for 90-120 min along with a transient period of mechanical hyperalgesia after sensory and motor block recovery.
High-performance liquid chromatography with electrochemical detection for the determination of levodopa, catecholamines and their metabolites in rat brain dialysates
Journal of Chromatography B: Biomedical Sciences and Applications, 1992
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.
Strategies to reduce aspecific adsorption of peptides and proteins in liquid chromatography-mass spectrometry based bioanalyses: an overview
Journal of chromatography. A, Jan 5, 2014
In the drug-discovery setting, the development of new peptide and protein-based biopharmaceutical... more In the drug-discovery setting, the development of new peptide and protein-based biopharmaceuticals attracts increased attention from the pharmaceutical industry and consequently demands the development of high-throughput LC-MS methods. Regulatory guidelines require bioanalytical methods to be validated not only in terms of linearity, sensitivity, accuracy, precision, selectivity and stability, but also in terms of carryover. Carryover results from the aspecific adsorption of analyte(s) to parts of the analytical system and thus introduces bias in both identification and quantification assays. Moreover, nonspecific binding occurs at the surface of materials used during sample preparation, such as pipette tips, sample tubes and LC-vials. Hence, linearity, sensitivity and repeatability of the analyses are negatively affected. Due to the great diversity in physicochemical properties of biomolecules, there is no general approach available to minimize adsorption phenomena. Therefore, we a...
Liquid chromatographic assay using a microcolumn coupled to a U-shaped optical cell for high-sensitivity ultraviolet absorbance detection of oxcarbazepine and its major metabolite in microdialysates
Journal of chromatography. B, Biomedical applications, Jan 6, 1995
An isocratic LC assay using a microcolumn (800 microns I.D.) coupled to a U-shaped optical flow c... more An isocratic LC assay using a microcolumn (800 microns I.D.) coupled to a U-shaped optical flow cell (cell volume 70 nl; optical path length 8 mm) for high-sensitivity UV absorbance is described for the detection of oxcarbazepine and its major and active metabolite, 10,11-dihydro-10-hydroxycarbamazepine in microdialysates. Using the combination microcolumn-capillary UV detector, a ten-fold increase in sensitivity was obtained resulting in a limit of detection of 10 pg/10 microliters. This assay is sufficiently sensitive to allow quantification of drug and metabolite in 10-microliters aliquots of rat blood and hippocampus microdialysates, using carbamazepine-10,11-epoxide as external standard.
Pharmaceutical research, 1995
In this study the microdialysis technique, using alpha-methyldopa as internal standard (IS), is i... more In this study the microdialysis technique, using alpha-methyldopa as internal standard (IS), is introduced for the in vivo determination of L-DOPA, dopamine (DA), and their metabolites dihydroxyphenylacetic acid (DOPAC) and 3-O-methyldopa (3-OMD) in blood plasma and skeletal muscle extracellular fluid (ECF), in anaesthetised beagle dogs, after i.v. administration of L-DOPA. In a first calibration experiment, the in vivo relative losses (RL) of the compounds and the IS were determined. These were lower in skeletal muscle than in blood plasma. K was defined as the ratio of the RL of the IS to the RL of the compound of interest and was shown to be constant for a certain compound within one tissue. However, except for DA, a significant difference was seen in K values between blood plasma and skeletal muscle. In a second step, the method was validated in blood plasma. The AUC0-->3 values for the non-protein bound L-DOPA did not differ significantly between the dialysis (141.3 +/- 16.0...
Longitudinal follow-up and characterization of a robust rat model for Parkinson's disease based on overexpression of alpha-synuclein with adeno-associated viral vectors
Neurobiology of aging, 2015
Testing of new therapeutic strategies for Parkinson's disease (PD) is currently hampered by t... more Testing of new therapeutic strategies for Parkinson's disease (PD) is currently hampered by the lack of relevant and reproducible animal models. Here, we developed a robust rat model for PD by injection of adeno-associated viral vectors (rAAV2/7) encoding α-synuclein into the substantia nigra, resulting in reproducible nigrostriatal pathology and behavioral deficits in a 4-week time period. Progressive dopaminergic dysfunction was corroborated by histopathologic and biochemical analysis, motor behavior testing and in vivo microdialysis. L-DOPA treatment was found to reverse the behavioral phenotype. Non-invasive positron emission tomography imaging and magnetic resonance spectroscopy allowed longitudinal monitoring of neurodegeneration. In addition, insoluble α-synuclein aggregates were formed in this model. This α-synuclein rat model shows improved face and predictive validity, and therefore offers the possibility to reliably test novel therapeutics. Furthermore, it will be of ...
The effect of carbidopa on the pharmacokinetics and metabolism of intravenously administered levodopa in blood plasma and skeletal muscle
The effect of carbidopa on the pharmacokinetics and metabolism of levodopa (L-dopa) in blood plas... more The effect of carbidopa on the pharmacokinetics and metabolism of levodopa (L-dopa) in blood plasma and skeletal muscle extracellular fluid (ECF) has been studied by repeated measurements in one beagle dog. The administration of a single dose of L-dopa (25 mg/kg i.v.) without carbidopa pretreatment (controls) resulted in an increase in the concentrations of L-dopa and 3-O-methyldopa (3-OMD) in blood plasma and skeletal muscle ECF dialysates. This effect was clearly potentiated for L-dopa in blood plasma (186% increase in AUC) and 3-OMD in skeletal muscle dialysates (108% increase in AUC) after pretreatment with carbidopa (100 mg/day). In addition, carbidopa prolonged the half-life of the elimination of L-dopa in blood plasma by 48% and in skeletal muscle ECF by 66% but did not influence its blood plasma distribution half-life (t 1/2 alpha = 0.17 h). The elimination half-life of L-dopa in the controls was higher in muscle (t 1/2 beta = 1.76 h) than in blood plasma (t 1/2 beta = 0.50 h). Carbidopa pretreatment resulted in a relatively small increase (29%) in the L-dopa content of skeletal muscle ECF as indicated by the AUC. The accumulation of 3-OMD in muscle dialysates, in contrast to that in plasma, was significantly enhanced after the administration of L-dopa following treatment with carbidopa. In the control experiments, dopamine (DA) was detectable only in the dialysates from muscle ECF.(ABSTRACT TRUNCATED AT 250 WORDS)
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Papers by Yvette Michotte