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Angelika Richter - One of the best experts on this subject based on the ideXlab platform.

  • Lower KV7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia.
    CNS & neurological disorders drug targets, 2016
    Co-Authors: Svenja E. Sander, Mustansir Diwan, Roger Raymond, José N. Nobrega, Angelika Richter
    Abstract:

    Dystonia is a hyperkinetic disabling movement disorder. In the dt(sz) hamster, a model of Paroxysmal Dystonia, pronounced antidystonic effects of the KV7.2-5 potassium channel opener retigabine and aggravation of Dystonia by a selective KV7.2-5 blocker indicated a pathophysiological role of an abnormal expression of KV7 channels. We therefore investigated the expression of KV7 subunits in brains of dystonic hamsters. While KV7.2 and KV7.3 subunits were unaltered, lower KV7.5 mRNA levels became evident in motor areas and in limbic structures of dystonic hamsters. The KV7.2/3 subunit-preferring channel opener N-(6-chloropyridin-3-yl)-3,4- difluorobenzamide (ICA 27243; 10-30 mg/kg i.p.) failed to reduce the severity of Dystonia in mutant hamsters, suggesting that the previously observed antidystonic action of retigabine is mediated by the activation of KV7.5 channels. The experiments indicate a functional relevance for KV7.5 channels in Paroxysmal Dystonia. We suggest that compounds highly selective for subtypes of KV7 channels, i.e. for KV7.5, may provide new therapeutic approaches.

  • Role of striatal NMDA receptor subunits in a model of Paroxysmal Dystonia
    Experimental neurology, 2014
    Co-Authors: Yosef Avchalumov, Melanie Hamann, Svenja E. Sander, Franziska Richter, Katrin Porath, Christoph Bode, Timo Kirschstein, Rüdiger Köhling, Angelika Richter
    Abstract:

    Abstract Dystonia is a movement disorder in which abnormal plasticity in the basal ganglia has been hypothesized to play a critical role. In a model of Paroxysmal Dystonia, the dt sz mutant hamster, previous studies indicated striatal dysfunctions, including an increased long-term potentiation (LTP). Beneficial effects were exerted by subunit-unspecific antagonists at NMDA receptors , which blocked LTP. NR2B subtype selective antagonists aggravated Dystonia after systemic treatment in dt sz hamsters, suggesting that beneficial effects involved the NR2A receptor subtype. In the present study, NVP-AAM077, an antagonist with preferential activity on NR2A-containing NMDA receptors, exerted significant antidystonic effects in mutant hamsters after systemic administration (20 and 30 mg/kg i.p.) and delayed the onset of a dystonic episode after intrastriatal injections (0.12 and 0.24 μg). As shown by present electrophysiological examinations in corticostriatal slices of dt sz hamsters and non-dystonic control hamsters, NVP-AAM077 (50 nM) completely blocked LTP in dt sz slices, but did not exert significant effects on LTP in non-dystonic controls. In contrast, the NR2B antagonist Ro 25-6981 (1–10 μmol) reduced LTP to a lower extent in dt sz mutant hamsters than in control animals. By using quantitative RT-PCR, the NR2A/NR2B ratio was found to be increased in the striatum, but not in the cortex of mutant hamsters in comparison to non-dystonic controls. These data indicate that NR2A-mediated activation may be involved in the pathophysiology of Paroxysmal Dystonia. Since significant antidystonic effects were observed after systemic administration of NVP-AAM077 already at well tolerated doses, antagonists with preferential activity on NR2A-containing NMDA receptors could be interesting candidates for the treatment of Dystonia.

  • Altered nicotinamide adenine dinucleotide (NADH) fluorescence in dt sz mutant hamsters reflects differences in striatal metabolism between severe and mild Dystonia
    Journal of neuroscience research, 2009
    Co-Authors: Melanie Hamann, Angelika Richter, Heidrun Fink, André Rex
    Abstract:

    The dt(sz) mutant hamster represents a unique rodent model of idiopathic Paroxysmal Dystonia. Previous data, collected post-mortem or in anesthetized hamsters under basal conditions, indicated the critical involvement of enhanced striatal neuronal activity. To assess the importance of an enhanced striatal neuronal activity directly during a dystonic episode, continuous monitoring of changes in brain metabolism and therefore neuronal activity indirectly in awake, freely moving animals is necessary. Determination of CNS metabolism by NADH measurement by laser-induced fluorescence spectroscopy in conscious dt(sz) and nondystonic control hamsters revealed reversible decreased NADH fluorescence during dystonic episodes. The degree of change corresponded to the severity of Dystonia. This study represents the first application of this innovative method in freely moving animals exhibiting a movement disorder. Our data clearly confirm that the expression of Paroxysmal Dystonia in dt(sz) mutant hamsters is associated with enhanced striatal neuronal activity and further underscore the versatile application of NADH fluorescence measurements in neuroscience.

  • Brivaracetam and seletracetam, two new SV2A ligands, improve Paroxysmal Dystonia in the dtsz mutant hamster
    European Journal of Pharmacology, 2008
    Co-Authors: Melanie Hamann, Svenja E. Sander, Angelika Richter
    Abstract:

    Previous examinations demonstrated antidystonic effects of the synaptic vesicle protein 2A (SV2A) ligand levetiracetam in the dt(sz) mutant hamster, an animal model of Paroxysmal non-kinesiogenic dyskinesia in which dystonic episodes can be induced by stress. In the present study, we examined the effects of the two new, high affinity SV2A ligands, brivaracetam and seletracetam, in comparison to levetiracetam on the severity of Dystonia in mutant hamsters. Seletracetam (50 and 75 mg/kg i.p.) and brivaracetam (75 mg/kg i.p.) reduced the severity of Dystonia to a comparable extent as levetiracetam (50 and 75 mg/kg i.p.). These data confirm the therapeutic potential of these pyrrolidone derivatives for the treatment of Paroxysmal Dystonia.

  • Brivaracetam and seletracetam, two new SV2A ligands, improve Paroxysmal Dystonia in the dt sz mutant hamster.
    European journal of pharmacology, 2008
    Co-Authors: Melanie Hamann, Svenja E. Sander, Angelika Richter
    Abstract:

    Previous examinations demonstrated antidystonic effects of the synaptic vesicle protein 2A (SV2A) ligand levetiracetam in the dt(sz) mutant hamster, an animal model of Paroxysmal non-kinesiogenic dyskinesia in which dystonic episodes can be induced by stress. In the present study, we examined the effects of the two new, high affinity SV2A ligands, brivaracetam and seletracetam, in comparison to levetiracetam on the severity of Dystonia in mutant hamsters. Seletracetam (50 and 75 mg/kg i.p.) and brivaracetam (75 mg/kg i.p.) reduced the severity of Dystonia to a comparable extent as levetiracetam (50 and 75 mg/kg i.p.). These data confirm the therapeutic potential of these pyrrolidone derivatives for the treatment of Paroxysmal Dystonia.

Melanie Hamann - One of the best experts on this subject based on the ideXlab platform.

  • Role of striatal NMDA receptor subunits in a model of Paroxysmal Dystonia
    Experimental neurology, 2014
    Co-Authors: Yosef Avchalumov, Melanie Hamann, Svenja E. Sander, Franziska Richter, Katrin Porath, Christoph Bode, Timo Kirschstein, Rüdiger Köhling, Angelika Richter
    Abstract:

    Abstract Dystonia is a movement disorder in which abnormal plasticity in the basal ganglia has been hypothesized to play a critical role. In a model of Paroxysmal Dystonia, the dt sz mutant hamster, previous studies indicated striatal dysfunctions, including an increased long-term potentiation (LTP). Beneficial effects were exerted by subunit-unspecific antagonists at NMDA receptors , which blocked LTP. NR2B subtype selective antagonists aggravated Dystonia after systemic treatment in dt sz hamsters, suggesting that beneficial effects involved the NR2A receptor subtype. In the present study, NVP-AAM077, an antagonist with preferential activity on NR2A-containing NMDA receptors, exerted significant antidystonic effects in mutant hamsters after systemic administration (20 and 30 mg/kg i.p.) and delayed the onset of a dystonic episode after intrastriatal injections (0.12 and 0.24 μg). As shown by present electrophysiological examinations in corticostriatal slices of dt sz hamsters and non-dystonic control hamsters, NVP-AAM077 (50 nM) completely blocked LTP in dt sz slices, but did not exert significant effects on LTP in non-dystonic controls. In contrast, the NR2B antagonist Ro 25-6981 (1–10 μmol) reduced LTP to a lower extent in dt sz mutant hamsters than in control animals. By using quantitative RT-PCR, the NR2A/NR2B ratio was found to be increased in the striatum, but not in the cortex of mutant hamsters in comparison to non-dystonic controls. These data indicate that NR2A-mediated activation may be involved in the pathophysiology of Paroxysmal Dystonia. Since significant antidystonic effects were observed after systemic administration of NVP-AAM077 already at well tolerated doses, antagonists with preferential activity on NR2A-containing NMDA receptors could be interesting candidates for the treatment of Dystonia.

  • Altered nicotinamide adenine dinucleotide (NADH) fluorescence in dt sz mutant hamsters reflects differences in striatal metabolism between severe and mild Dystonia
    Journal of neuroscience research, 2009
    Co-Authors: Melanie Hamann, Angelika Richter, Heidrun Fink, André Rex
    Abstract:

    The dt(sz) mutant hamster represents a unique rodent model of idiopathic Paroxysmal Dystonia. Previous data, collected post-mortem or in anesthetized hamsters under basal conditions, indicated the critical involvement of enhanced striatal neuronal activity. To assess the importance of an enhanced striatal neuronal activity directly during a dystonic episode, continuous monitoring of changes in brain metabolism and therefore neuronal activity indirectly in awake, freely moving animals is necessary. Determination of CNS metabolism by NADH measurement by laser-induced fluorescence spectroscopy in conscious dt(sz) and nondystonic control hamsters revealed reversible decreased NADH fluorescence during dystonic episodes. The degree of change corresponded to the severity of Dystonia. This study represents the first application of this innovative method in freely moving animals exhibiting a movement disorder. Our data clearly confirm that the expression of Paroxysmal Dystonia in dt(sz) mutant hamsters is associated with enhanced striatal neuronal activity and further underscore the versatile application of NADH fluorescence measurements in neuroscience.

  • Brivaracetam and seletracetam, two new SV2A ligands, improve Paroxysmal Dystonia in the dt sz mutant hamster.
    European journal of pharmacology, 2008
    Co-Authors: Melanie Hamann, Svenja E. Sander, Angelika Richter
    Abstract:

    Previous examinations demonstrated antidystonic effects of the synaptic vesicle protein 2A (SV2A) ligand levetiracetam in the dt(sz) mutant hamster, an animal model of Paroxysmal non-kinesiogenic dyskinesia in which dystonic episodes can be induced by stress. In the present study, we examined the effects of the two new, high affinity SV2A ligands, brivaracetam and seletracetam, in comparison to levetiracetam on the severity of Dystonia in mutant hamsters. Seletracetam (50 and 75 mg/kg i.p.) and brivaracetam (75 mg/kg i.p.) reduced the severity of Dystonia to a comparable extent as levetiracetam (50 and 75 mg/kg i.p.). These data confirm the therapeutic potential of these pyrrolidone derivatives for the treatment of Paroxysmal Dystonia.

  • Brivaracetam and seletracetam, two new SV2A ligands, improve Paroxysmal Dystonia in the dtsz mutant hamster
    European Journal of Pharmacology, 2008
    Co-Authors: Melanie Hamann, Svenja E. Sander, Angelika Richter
    Abstract:

    Previous examinations demonstrated antidystonic effects of the synaptic vesicle protein 2A (SV2A) ligand levetiracetam in the dt(sz) mutant hamster, an animal model of Paroxysmal non-kinesiogenic dyskinesia in which dystonic episodes can be induced by stress. In the present study, we examined the effects of the two new, high affinity SV2A ligands, brivaracetam and seletracetam, in comparison to levetiracetam on the severity of Dystonia in mutant hamsters. Seletracetam (50 and 75 mg/kg i.p.) and brivaracetam (75 mg/kg i.p.) reduced the severity of Dystonia to a comparable extent as levetiracetam (50 and 75 mg/kg i.p.). These data confirm the therapeutic potential of these pyrrolidone derivatives for the treatment of Paroxysmal Dystonia.

  • Extracellular amino acid levels in the striatum of the dtsz mutant, a model of Paroxysmal Dystonia
    Neuroscience, 2008
    Co-Authors: Melanie Hamann, R. Sohr, Rudolf Morgenstern, Angelika Richter
    Abstract:

    The pathophysiology of idiopathic Dystonia is still unknown, but it is regarded as a basal ganglia disorder. Previous studies indicated an involvement of a striatal GABAergic disinhibition and a cortico-striatal glutamatergic overactivity in the manifestation of stress-inducible dystonic episodes in the dt(sz) hamster, a model of idiopathic Paroxysmal Dystonia. These investigations were carried out postmortem or in anesthetized animals. In the present study, in vivo microdialysis in conscious, freely-moving dt(sz) and non-dystonic control hamsters was used to examine the levels of GABA, aspartate, glutamate, glutamine, glycine and taurine in each animal during following conditions: (1) at baseline in the absence of Dystonia, (2) during an episode of Paroxysmal Dystonia precipitated by stressful stimuli, (3) during a recovery period and (4) at baseline after complete recovery. In comparison to non-dystonic controls, which were treated in the same manner as the dystonic animals, no differences could be detected under basal conditions. The induction of a dystonic episode in mutant hamsters led to higher contents of glycine in these animals in comparison to stressed but non-dystonic controls. Significant changes of glycine levels within the animal groups were not detected. The levels of the excitatory amino acids glutamate, glutamine and aspartate as well as the levels of the inhibitory amino acids GABA and taurine did not differ between the animal groups or between the periods of measurement. The higher levels of glycine might contribute to the manifestation of Paroxysmal Dystonia in dt(sz) hamsters, although unaltered glutamate, glutamine and aspartate levels do not support the hypothesis of a critical involvement of a cortico-striatal overactivity. It seems that a deficiency of GABAergic interneurons, found by previous immunohistochemical examinations, does not lead to reduced extracellular GABA levels in the striatum.

Wolfgang Loscher - One of the best experts on this subject based on the ideXlab platform.

  • Deficit of Striatal Parvalbumin-Reactive GABAergic Interneurons and Decreased Basal Ganglia Output in a Genetic Rodent Model of Idiopathic Paroxysmal Dystonia
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
    Co-Authors: Manuela Gernert, Wolfgang Loscher, Melanie Hamann, Mustapha Bennay, Angelika Richter
    Abstract:

    The underlying mechanisms of various types of hereditary Dystonia, a common movement disorder, are still unknown. Recent findings in a genetic model of a type of Paroxysmal Dystonia, thedtsz mutant hamster, pointed to striatal dysfunctions. In the present study, immunhistochemical experiments demonstrated a marked decrease in the number and density of parvalbumin-immunoreactive GABAergic interneurons in all striatal subregions of mutant hamsters. To examine the functional relevance of the reduction of these inhibitory interneurons, the effects of the GABAA receptor agonist muscimol on severity of Dystonia were examined after microinjections into the striatum and after systemic administrations. Muscimol improved the dystonic syndrome after striatal injections to a similar extent as after systemic treatment, supporting the importance of the deficiency of striatal GABAergic interneurons for the occurrence of the motor disturbances. The disinhibition of striatal GABAergic projection neurons, as suggested by recent extracellular single-unit recordings indtsz hamsters, should lead to an abnormal neuronal activity in the basal ganglia output nuclei. Indeed, a significantly decreased basal discharge rate of entopeduncular neurons was found in dtsz hamsters. We conclude that a deficit of striatal GABAergic interneurons leads by disinhibition of striatal GABAergic projection neurons to a reduced activity in the entopeduncular nucleus, i.e., to a decreased basal ganglia output. This finding is in line with the current hypothesis about the pathophysiology of hyperkinesias. The results indicate that striatal interneurons deserve attention in basic and clinical research of those movement disorders.

  • Antidystonic efficacy of nitric oxide synthase inhibitors in a rodent model of primary Paroxysmal Dystonia.
    British journal of pharmacology, 2000
    Co-Authors: Angelika Richter, Peter-a. Löschmann, Wolfgang Loscher
    Abstract:

    In a hamster model (genetic symbol dtsz) of primary Paroxysmal non-kinesiogenic dystonic choreoathetosis, recent studies have shown beneficial effects of glutamate and dopamine receptor antagonists. Nitric oxide (NO), synthesized from L-arginine by NO synthase in response to glutamate receptor activation, elicits cyclic GMP and modulates glutamate-mediated processes and striatal dopamine release. Therefore, the effects of NO synthase inhibitors and of L-arginine on severity of Dystonia were investigated in dtsz hamsters in which dystonic attacks, characterized by twisting movements and postures, can be induced by stress. The NO synthase inhibitors NG-nitro-L-arginine (L-NNA), NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole significantly reduced the severity of Dystonia. At antidystonic effective doses neither L-NNA nor L-NAME caused observable side effects, whereas 7-nitroindazole exerted moderate reduction of locomotor activity. The antidystonic effect of L-NAME was reversed by co-administration of the NO precursor L-arginine. However, L-arginine administered alone did not exert any effect on severity of Dystonia. Cerebellar cyclic GMP levels in brains of mutant hamsters in comparison to non-dystonic control hamsters did not significantly differ, but the cerebellar cyclic GMP levels tended to be increased in dtsz hamsters during a dystonic attack. L-NAME significantly decreased the cerebellar cyclic GMP levels in both dtsz and control hamsters. Although an overproduction of NO is probably not critically involved in the pathogenesis of Paroxysmal Dystonia, it may contribute to the manifestation of dystonic attacks, as indicated by the antidystonic effects of NO synthase inhibitors. Peripheral side effects may limit the clinical use of NO synthase inhibitors, but more selective inhibitors of the neuronal NO synthase should be considered as interesting candidates for the treatment of Paroxysmal Dystonia. British Journal of Pharmacology (2000) 131, 921–926; doi:10.1038/sj.bjp.0703609

  • Tyrosine hydroxylase immunoreactivity and [3H]WIN 35,428 binding to the dopamine transporter in a hamster model of idiopathic Paroxysmal Dystonia
    Neuroscience, 1999
    Co-Authors: José N. Nobrega, Manuela Gernert, Wolfgang Loscher, Roger Raymond, T. Belej, Angelika Richter
    Abstract:

    Recent pharmacological studies and receptor analyses have suggested that dopamine neurotransmission is enhanced in mutant dystonic hamsters (dt(sz)), a model of idiopathic Paroxysmal Dystonia which displays attacks of generalized Dystonia in response to mild stress. In order to further characterize the nature of dopamine alterations, the present study investigated possible changes in the number of dopaminergic neurons, as defined by tyrosine hydroxylase immunohistochemistry, as well as binding to the dopamine transporter labelled with [3H]WIN 35,428 in dystonic hamsters. No differences in the number of tyrosine hydroxylase-immunoreactive neurons were found within the substantia nigra and ventral tegmental area of mutant hamsters compared to non-dystonic control hamsters. Similarly, under basal conditions, i.e. in the absence of a dystonic episode, no significant changes in [3H]WIN 35,428 binding were detected in dystonic brains. However, in animals killed during the expression of severe Dystonia, significant decreases in dopamine transporter binding became evident in the nucleus accumbens and ventral tegmental area in comparison to controls exposed to the same external stimulation. Since stimulation tended to increase [3H]WIN 35,428 binding in control brains, the observed decrease in the ventral tegmental area appeared to be due primarily to the fact that binding was increased less in dystonic brains than in similarly stimulated control animals. This finding could reflect a diminished ability of the dopamine transporter to undergo adaptive changes in response to external stressful stimulation in mutant hamsters. The selective dopamine uptake inhibitor GBR 12909 (20 mg/kg) aggravated Dystonia in mutant hamsters, further suggesting that acute alterations in dopamine transporter function during stimulation may be an important component of Dystonia in this model.

  • quantitative eeg analysis of depth electrode recordings from several brain regions of mutant hamsters with Paroxysmal Dystonia discloses frequency changes in the basal ganglia
    Movement Disorders, 1998
    Co-Authors: Manuela Gernert, Angelika Richter, Chris Rundfeldt, Wolfgang Loscher
    Abstract:

    : Computerized EEG spectral analyses of depth electrode recordings from striatum (caudate/putamen; CPu), globus pallidus (GP), and parietal cortex (pCtx) were performed before and after dystonic attacks in freely moving mutant dt(sz) hamsters with Paroxysmal Dystonia. In these hamsters, sustained attacks of abnormal movements and postures can be reproducibly induced by stress, such as placing the animals in a new environment. Data recorded from mutant hamsters were compared with recordings from age-matched nondystonic control hamsters. The predominant EEG changes in CPu and GP of dystonic hamsters were significant decreases in the high-frequency beta2 range and there was a tendency to increase in delta and theta activities. These changes were seen both before and after onset of dystonic attacks, indicating a permanent disturbance of neural activities in the basal ganglia of dystonic animals. No such changes were seen in the pCtx. Furthermore, no epileptic or epileptiform activity was seen in any of the recordings, substantiating a previous notion from cortical and hippocampal recordings that Paroxysmal Dystonia in these mutant hamsters has no epileptogenic basis. The present finding of abnormal synchronization of neural activity in the CPu and GP of dystonic hamsters adds to the belief that the striatopallidal-thalamocortical circuit is the most likely site in which to search for the unknown defect in primary (idiopathic) Dystonia. As suggested by this study, quantitative EEG analysis can increase the likelihood of detecting subtle EEG abnormalities in different types of idiopathic Dystonia and thereby improves our understanding of the pathogenetic mechanisms of this movement disorder.

  • Alterations in the brain GABAA/benzodiazepine receptor-chloride ionophore complex in a genetic model of Paroxysmal Dystonia: A quantitative autoradiographic analysis
    Neuroscience, 1995
    Co-Authors: José N. Nobrega, Angelika Richter, W.m. Burnham, Wolfgang Loscher
    Abstract:

    Dystonia is a relatively common syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The most frequent type of Dystonia is idiopathic generalized Dystonia, whose pathophysiology is largely unknown. In this respect, mutant animal strains with inborn Dystonia may be helpful to elucidate the pathophysiological defects involved in idiopathic Dystonia. The genetically dystonic (dtsz) hamster is an animal model of Paroxysmal Dystonia that displays attacks of generalized Dystonia either spontaneously or in response to mild environmental stimuli. In the present study, a quantitative autoradiographic analysis of ligand binding to different sites of the GABAA/benzodiazepine receptor-chloride ionophore complex was carried out in 123 brain areas from genetically dystonic mutant hamsters and age-matched control hamsters. Animals were killed 2 weeks after their last dystonic attack. Analysis of the GABA-binding site of the receptor complex, using the ligand [3H]muscimol, and the benzodiazepine site labelled with [3H]flunitrazepam revealed no significant alterations in the binding of either ligand in any of the brain regions examined. In contrast, widespread changes were observed in binding densities of [35S]t-butylbicyclophosphorothionate ([35S]t-butylbicyclophosphorothionate), which labels the picrotoxinin site of the GABAA receptor-chloride ionophore complex. Significantly increased [35S]t-butylbicyclophosphorothionate binding was found in several parts of the thalamus, cortex, and hippocampus as well as in the red nucleus, the subthalamic nucleus, and the granular layer of the cerebellum. Since high-affinity [35S]TBPS binding is thought to represent the closed conformation of the GABA-gated chloride ionophore, increased TBPS binding would indicate an impaired GABAergic function. The study is consistent with the concept that Dystonia is caused by impaired connections between the basal ganglia, the thalamus, and frontal association areas. The data on increased [35S]TBPS binding are the first evidence implicating alterations in the GABA-gated chloride ion channel function in a movement disorder, i.e. idiopathic generalized Dystonia.

José N. Nobrega - One of the best experts on this subject based on the ideXlab platform.

  • Lower KV7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia.
    CNS & neurological disorders drug targets, 2016
    Co-Authors: Svenja E. Sander, Mustansir Diwan, Roger Raymond, José N. Nobrega, Angelika Richter
    Abstract:

    Dystonia is a hyperkinetic disabling movement disorder. In the dt(sz) hamster, a model of Paroxysmal Dystonia, pronounced antidystonic effects of the KV7.2-5 potassium channel opener retigabine and aggravation of Dystonia by a selective KV7.2-5 blocker indicated a pathophysiological role of an abnormal expression of KV7 channels. We therefore investigated the expression of KV7 subunits in brains of dystonic hamsters. While KV7.2 and KV7.3 subunits were unaltered, lower KV7.5 mRNA levels became evident in motor areas and in limbic structures of dystonic hamsters. The KV7.2/3 subunit-preferring channel opener N-(6-chloropyridin-3-yl)-3,4- difluorobenzamide (ICA 27243; 10-30 mg/kg i.p.) failed to reduce the severity of Dystonia in mutant hamsters, suggesting that the previously observed antidystonic action of retigabine is mediated by the activation of KV7.5 channels. The experiments indicate a functional relevance for KV7.5 channels in Paroxysmal Dystonia. We suggest that compounds highly selective for subtypes of KV7 channels, i.e. for KV7.5, may provide new therapeutic approaches.

  • Acetylcholine receptor binding and cholinergic interneuron density are unaltered in a genetic animal model of primary Paroxysmal Dystonia
    Brain research, 2006
    Co-Authors: Melanie Hamann, Roger Raymond, José N. Nobrega, Suneel Varughesi, Angelika Richter
    Abstract:

    Abstract The underlying pathophysiological mechanisms of hereditary types of Paroxysmal dyskinesias are still unknown, but basal ganglia dysfunctions seem to play a critical role. In fact, numerous pharmacological, neurochemical, immunohistochemical and electrophysiological investigations in the dtsz hamsters, a unique rodent model of age-dependent primary Paroxysmal Dystonia, revealed alterations within the basal ganglia, particularly of the GABAergic and dopaminergic neurotransmitter systems. A deficit in several types of striatal GABAergic interneurons in dtsz mutant hamsters seems to play a crucial pathophysiological role, but deficits in other types of striatal interneurons cannot be excluded by previous studies. In view of ameliorating effects of anti-cholinergic drugs in dystonic patients, we therefore investigated the density of striatal cholinergic interneurons in the present study. These interneurons were marked specifically by the enzyme choline acetyltransferase and counted by using a stereological counting method in a blinded fashion. Additionally, acetylcholine receptor binding was determined in mutant and nondystonic control hamsters by autoradiographic analyses with the nonselective muscarinic ligand [3H]-quinuclidinyl benzilate (QNB) in 11 brain (sub)regions. There were no significant differences in the density of striatal cholinergic interneurons between dtsz mutant hamsters (789 ± 39 interneurons/mm3) and nondystonic controls (807 ± 36 interneurons/mm3). [3H]QNB binding was also comparable between mutant and control hamsters. These results point to an unaltered striatal cholinergic neurotransmitter system in dtsz hamsters under basal conditions.

  • Changes in AMPA receptor binding in an animal model of inborn Paroxysmal Dystonia.
    Experimental neurology, 2002
    Co-Authors: José N. Nobrega, Roger Raymond, Melanie Hamann, Karen B. L. Barlow, Angelika Richter
    Abstract:

    Abstract Previous pharmacological studies suggested that glutamatergic overactivity contributes to manifestation of dystonic attacks in mutant hamsters ( dt sz ), a model of idiopathic Paroxysmal Dystonia in which episodes of Dystonia occur in response to stress. In the present study, [ 3 H]AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionate) receptor binding was determined by autoradiographic analyses in 41 brain (sub)regions of dt sz hamsters under basal conditions, i.e., in the absence of Dystonia, and in a group of mutant hamsters that exhibited severe stress-induced dystonic attacks immediately prior to sacrifice. In comparison to nondystonic control hamsters the basal [ 3 H]AMPA binding was significantly higher in the ventromedial and ventrolateral caudate putamen, the anterior cingulate cortex, the hippocampus, and the lateral septum of dystonic brains. During dystonic attacks the [ 3 H]AMPA binding was significantly lower in the dorsomedial, dorsolateral, and posterior caudate putamen; the ventromedial thalamus; and the frontal cortex of mutant hamsters compared with control animals that were exposed to the same external stimulation. The basal increase in AMPA receptor density within limbic structures may contribute to the susceptibility of stress-inducible dystonic episodes in mutant hamsters. Since AMPA receptor activation is known to cause a fast reduction of the affinity and an internalization of postsynaptic AMPA receptors, the latter finding could reflect a glutamatergic overactivity within the striato-thalamo-cortical circuit during the expression of Dystonia, which is in line with previous neurochemical and pharmacological data in dt sz hamsters.

  • Tyrosine hydroxylase immunoreactivity and [3H]WIN 35,428 binding to the dopamine transporter in a hamster model of idiopathic Paroxysmal Dystonia
    Neuroscience, 1999
    Co-Authors: José N. Nobrega, Manuela Gernert, Wolfgang Loscher, Roger Raymond, T. Belej, Angelika Richter
    Abstract:

    Recent pharmacological studies and receptor analyses have suggested that dopamine neurotransmission is enhanced in mutant dystonic hamsters (dt(sz)), a model of idiopathic Paroxysmal Dystonia which displays attacks of generalized Dystonia in response to mild stress. In order to further characterize the nature of dopamine alterations, the present study investigated possible changes in the number of dopaminergic neurons, as defined by tyrosine hydroxylase immunohistochemistry, as well as binding to the dopamine transporter labelled with [3H]WIN 35,428 in dystonic hamsters. No differences in the number of tyrosine hydroxylase-immunoreactive neurons were found within the substantia nigra and ventral tegmental area of mutant hamsters compared to non-dystonic control hamsters. Similarly, under basal conditions, i.e. in the absence of a dystonic episode, no significant changes in [3H]WIN 35,428 binding were detected in dystonic brains. However, in animals killed during the expression of severe Dystonia, significant decreases in dopamine transporter binding became evident in the nucleus accumbens and ventral tegmental area in comparison to controls exposed to the same external stimulation. Since stimulation tended to increase [3H]WIN 35,428 binding in control brains, the observed decrease in the ventral tegmental area appeared to be due primarily to the fact that binding was increased less in dystonic brains than in similarly stimulated control animals. This finding could reflect a diminished ability of the dopamine transporter to undergo adaptive changes in response to external stressful stimulation in mutant hamsters. The selective dopamine uptake inhibitor GBR 12909 (20 mg/kg) aggravated Dystonia in mutant hamsters, further suggesting that acute alterations in dopamine transporter function during stimulation may be an important component of Dystonia in this model.

  • Alterations in the brain GABAA/benzodiazepine receptor-chloride ionophore complex in a genetic model of Paroxysmal Dystonia: A quantitative autoradiographic analysis
    Neuroscience, 1995
    Co-Authors: José N. Nobrega, Angelika Richter, W.m. Burnham, Wolfgang Loscher
    Abstract:

    Dystonia is a relatively common syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The most frequent type of Dystonia is idiopathic generalized Dystonia, whose pathophysiology is largely unknown. In this respect, mutant animal strains with inborn Dystonia may be helpful to elucidate the pathophysiological defects involved in idiopathic Dystonia. The genetically dystonic (dtsz) hamster is an animal model of Paroxysmal Dystonia that displays attacks of generalized Dystonia either spontaneously or in response to mild environmental stimuli. In the present study, a quantitative autoradiographic analysis of ligand binding to different sites of the GABAA/benzodiazepine receptor-chloride ionophore complex was carried out in 123 brain areas from genetically dystonic mutant hamsters and age-matched control hamsters. Animals were killed 2 weeks after their last dystonic attack. Analysis of the GABA-binding site of the receptor complex, using the ligand [3H]muscimol, and the benzodiazepine site labelled with [3H]flunitrazepam revealed no significant alterations in the binding of either ligand in any of the brain regions examined. In contrast, widespread changes were observed in binding densities of [35S]t-butylbicyclophosphorothionate ([35S]t-butylbicyclophosphorothionate), which labels the picrotoxinin site of the GABAA receptor-chloride ionophore complex. Significantly increased [35S]t-butylbicyclophosphorothionate binding was found in several parts of the thalamus, cortex, and hippocampus as well as in the red nucleus, the subthalamic nucleus, and the granular layer of the cerebellum. Since high-affinity [35S]TBPS binding is thought to represent the closed conformation of the GABA-gated chloride ionophore, increased TBPS binding would indicate an impaired GABAergic function. The study is consistent with the concept that Dystonia is caused by impaired connections between the basal ganglia, the thalamus, and frontal association areas. The data on increased [35S]TBPS binding are the first evidence implicating alterations in the GABA-gated chloride ion channel function in a movement disorder, i.e. idiopathic generalized Dystonia.

Svenja E. Sander - One of the best experts on this subject based on the ideXlab platform.

  • Lower KV7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia.
    CNS & neurological disorders drug targets, 2016
    Co-Authors: Svenja E. Sander, Mustansir Diwan, Roger Raymond, José N. Nobrega, Angelika Richter
    Abstract:

    Dystonia is a hyperkinetic disabling movement disorder. In the dt(sz) hamster, a model of Paroxysmal Dystonia, pronounced antidystonic effects of the KV7.2-5 potassium channel opener retigabine and aggravation of Dystonia by a selective KV7.2-5 blocker indicated a pathophysiological role of an abnormal expression of KV7 channels. We therefore investigated the expression of KV7 subunits in brains of dystonic hamsters. While KV7.2 and KV7.3 subunits were unaltered, lower KV7.5 mRNA levels became evident in motor areas and in limbic structures of dystonic hamsters. The KV7.2/3 subunit-preferring channel opener N-(6-chloropyridin-3-yl)-3,4- difluorobenzamide (ICA 27243; 10-30 mg/kg i.p.) failed to reduce the severity of Dystonia in mutant hamsters, suggesting that the previously observed antidystonic action of retigabine is mediated by the activation of KV7.5 channels. The experiments indicate a functional relevance for KV7.5 channels in Paroxysmal Dystonia. We suggest that compounds highly selective for subtypes of KV7 channels, i.e. for KV7.5, may provide new therapeutic approaches.

  • Role of striatal NMDA receptor subunits in a model of Paroxysmal Dystonia
    Experimental neurology, 2014
    Co-Authors: Yosef Avchalumov, Melanie Hamann, Svenja E. Sander, Franziska Richter, Katrin Porath, Christoph Bode, Timo Kirschstein, Rüdiger Köhling, Angelika Richter
    Abstract:

    Abstract Dystonia is a movement disorder in which abnormal plasticity in the basal ganglia has been hypothesized to play a critical role. In a model of Paroxysmal Dystonia, the dt sz mutant hamster, previous studies indicated striatal dysfunctions, including an increased long-term potentiation (LTP). Beneficial effects were exerted by subunit-unspecific antagonists at NMDA receptors , which blocked LTP. NR2B subtype selective antagonists aggravated Dystonia after systemic treatment in dt sz hamsters, suggesting that beneficial effects involved the NR2A receptor subtype. In the present study, NVP-AAM077, an antagonist with preferential activity on NR2A-containing NMDA receptors, exerted significant antidystonic effects in mutant hamsters after systemic administration (20 and 30 mg/kg i.p.) and delayed the onset of a dystonic episode after intrastriatal injections (0.12 and 0.24 μg). As shown by present electrophysiological examinations in corticostriatal slices of dt sz hamsters and non-dystonic control hamsters, NVP-AAM077 (50 nM) completely blocked LTP in dt sz slices, but did not exert significant effects on LTP in non-dystonic controls. In contrast, the NR2B antagonist Ro 25-6981 (1–10 μmol) reduced LTP to a lower extent in dt sz mutant hamsters than in control animals. By using quantitative RT-PCR, the NR2A/NR2B ratio was found to be increased in the striatum, but not in the cortex of mutant hamsters in comparison to non-dystonic controls. These data indicate that NR2A-mediated activation may be involved in the pathophysiology of Paroxysmal Dystonia. Since significant antidystonic effects were observed after systemic administration of NVP-AAM077 already at well tolerated doses, antagonists with preferential activity on NR2A-containing NMDA receptors could be interesting candidates for the treatment of Dystonia.

  • Brivaracetam and seletracetam, two new SV2A ligands, improve Paroxysmal Dystonia in the dtsz mutant hamster
    European Journal of Pharmacology, 2008
    Co-Authors: Melanie Hamann, Svenja E. Sander, Angelika Richter
    Abstract:

    Previous examinations demonstrated antidystonic effects of the synaptic vesicle protein 2A (SV2A) ligand levetiracetam in the dt(sz) mutant hamster, an animal model of Paroxysmal non-kinesiogenic dyskinesia in which dystonic episodes can be induced by stress. In the present study, we examined the effects of the two new, high affinity SV2A ligands, brivaracetam and seletracetam, in comparison to levetiracetam on the severity of Dystonia in mutant hamsters. Seletracetam (50 and 75 mg/kg i.p.) and brivaracetam (75 mg/kg i.p.) reduced the severity of Dystonia to a comparable extent as levetiracetam (50 and 75 mg/kg i.p.). These data confirm the therapeutic potential of these pyrrolidone derivatives for the treatment of Paroxysmal Dystonia.

  • Brivaracetam and seletracetam, two new SV2A ligands, improve Paroxysmal Dystonia in the dt sz mutant hamster.
    European journal of pharmacology, 2008
    Co-Authors: Melanie Hamann, Svenja E. Sander, Angelika Richter
    Abstract:

    Previous examinations demonstrated antidystonic effects of the synaptic vesicle protein 2A (SV2A) ligand levetiracetam in the dt(sz) mutant hamster, an animal model of Paroxysmal non-kinesiogenic dyskinesia in which dystonic episodes can be induced by stress. In the present study, we examined the effects of the two new, high affinity SV2A ligands, brivaracetam and seletracetam, in comparison to levetiracetam on the severity of Dystonia in mutant hamsters. Seletracetam (50 and 75 mg/kg i.p.) and brivaracetam (75 mg/kg i.p.) reduced the severity of Dystonia to a comparable extent as levetiracetam (50 and 75 mg/kg i.p.). These data confirm the therapeutic potential of these pyrrolidone derivatives for the treatment of Paroxysmal Dystonia.

  • Age-dependent alterations of striatal calretinin interneuron density in a genetic animal model of primary Paroxysmal Dystonia.
    Journal of neuropathology and experimental neurology, 2005
    Co-Authors: Melanie Hamann, Svenja E. Sander, Angelika Richter
    Abstract:

    Various types of hereditary Dystonia are regarded as a basal ganglia disorder, but the underlying mechanisms are still unknown. In the dt hamster, a genetic animal model of age-dependent Paroxysmal Dystonia, recent studies demonstrated a reduced density of striatal parvalbumin-immunoreactive (PV) GABAergic interneurons at an age of maximum severity of Dystonia in comparison with age-matched nondystonic controls. So far, alterations of other types of striatal interneurons in dt hamsters cannot be excluded. Therefore, we determined the density of calretinin-immunoreactive (CR) interneurons in the dt mutant at an age of maximum severity and after spontaneous remission of Dystonia in comparison with age-matched nondystonic controls using an image analysis system and a stereologic counting method in a blinded fashion. At an age of maximum severity of Dystonia, CR interneuron density was significantly lower in dt hamsters in comparison with controls (-20%), whereas no significant differences between the animal groups could be detected after spontaneous remission of Dystonia. The comparison of CR interneuron density between young hamsters with those at an age of > 90 days revealed a significant ontogenetic decrease of CR interneurons in both animal groups (dt hamsters: -38%, controls: -54%). These results demonstrate that alterations of striatal interneuron density in dt mutants are not restricted to PV ones. A deficit of CR interneurons that coexpress GABA may contribute to previous findings of disinhibition of striatal projection neurons in the dt mutant at an age of maximum expression of Dystonia.