Angelika Richter

....

..The antidystonic efficacy of Ro 61-8048 at well-tolerated doses suggests that kynurenine 3-hydroxylase inhibitors should be considered as new therapeutic candidates for the treatment of dyskinesias...

..The mechanism of the antidystonic efficacy of acetazolamide has to be examined by further studies...

..Paroxysmal dyskinesias with dystonia are a group of movement disorders which are regarded as ion channelopathies, but the role of Kv7 channels in the pathogenesis and as targets for the treatment have so far not been examined...

..Nevertheless, previously found changes in entopeduncular activity probably play a critical pathophysiological role in dystonic hamsters...

..However, the extent of the neuronal loss was moderate and the technical expense limits the utility as a subchronic model...

..Interestingly, prepulse inhibition was absent in mutant hamsters. The latter finding suggests a disturbed sensorimotor gating that can be related to alterations in both the basal ganglia nuclei and in limbic structures...

..The present data suggest that a retarded postnatal maturation of striatal PV(+) interneurons plays a critical role in paroxysmal dystonia...

..These results suggest that periodic elevations of dopamine levels in these animals are not related to D3 receptor dysfunctions...

....

..Therefore, corticostriatal glutamatergic overactivity mediated by AMPA receptors, but not by NMDA receptors, is possibly important for the manifestation of dystonic attacks in the dtsz hamster mutant...

..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...

..Future studies have to include measurements of brain neurosteroid levels as well as of chronic neurosteroid administrations to clarify the pathophysiological role and therapeutic potential of neurosteroids in dystonia...

....

..3)H]QNB binding was also comparable between mutant and control hamsters. These results point to an unaltered striatal cholinergic neurotransmitter system in dt(sz) hamsters under basal conditions...

..In view of previous pathophysiological findings in mutant hamsters, the antidystonic efficacy of WIN 55,212-2 can be explained by modulation of different neurotransmitter systems within the basal ganglia...

..Consistent with previous pharmacologic findings, paroxysmal dystonia in mutant hamsters is associated with temporary increases of extracellular dopamine levels in the striatum...

..These data indicate that disturbed rubral GABAergic inhibition is not important for the manifestation of dystonia in the dt(sz) mutant...

....

..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...

....

..NR2B-selective NMDA receptor antagonists seem not to provide a novel approach in the treatment of hereditary paroxysmal dyskinesias...

..It seems that a deficiency of GABAergic interneurons, found by previous immunohistochemical examinations, does not lead to reduced extracellular GABA levels in the striatum...

..In view of the absence of striatal changes in GABA(B) binding, the strong antidystonic effect of baclofen after its striatal microinjection is probably related to a suppression of a pathophysiologically increased synaptic activity...

..p.) significantly reduced the severity of dystonia. These data suggest that GABA uptake inhibitors may provide novel therapeutic approaches for paroxysmal dyskinesias...

..The consequentially enhanced striato-entopeduncular inhibition leads to an already evidenced reduced activity and an altered firing pattern of entopeduncular neurons in the dt(sz) hamster...

..Our results underline the pathophysiological role of the EPN in the dtsz hamster and suggest the suitability of this model to further investigate mechanisms of HFS in dystonia...

..With the exception of muscle weakness, many of the features of the med(J) mouse are similar to human idiopathic dystonia...

....

..The age-related deficit of NOS-reactive interneurones may at least in part contribute to an abnormal activity of striatal GABAergic projection neurones and thereby to the age-dependent dystonic syndrome in the dt(sz) mutant...

..Further studies will have to clarify whether genetic mouse models of PD might be more sensitive to the neurotoxic effects of rotenone...

..Therefore, these data do not provide clear evidence for dysfunctions of the dopaminergic system in this mouse model...

..Therefore, this method represents a useful tool in the 3R concept, since replacement of invasive tissue sampling refines the use of transgenic mice...

..In view of recent findings, we assume that GABAergic dysfunctions in dystonic hamsters are of regionally different extent...

..The GABApotentiating activity of gabapentin could explain the antidystonic effects of low doses, while the loss of efficacy at higher doses may be due to other mechanisms of gabapentin...

....

..Tentatively, activity-dependent GABA-mediated excitation caused by chronic treatment with phenobarbital may be important for the prodystonic effects under pathological conditions in dt(sz) hamsters...

....

..Although the observed changes of neural activity in the RN are probably based on a primary dysfunction in related structures, the present data demonstrate its importance in the expression of dystonic movements...

..In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder...

..The antidystonic activity of piracetam and levetiracetam was not associated with any behavioral side effects. The data indicate that piracetam and levetiracetam are interesting novel treatments for idiopathic dystonia...

..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...

..Apart from the use of ci3 rats for studying the functional lateralization of brain functions, the ci3 mutant may serve as a new model for movement disorders with abnormal lateralization...

..The greater susceptibility of neurons within the SNr to PTZ suggests dysfunctions of the GABA(A) receptor in dt(sz) mutants...

..These results provide insights into the pathophysiology of early-onset dystonia and strengthen links between the dopaminergic system and dystonia...

..In summary, the study indicates that a change of cortico-striatal communication is involved in the manifestation of paroxysmal dystonia in the dt(sz) mutant...

..In all, the present data substantiate the relevance of striatal GABAergic disinhibition in the pathogenesis of paroxysmal dystonia in dt(sz) mutants...

..To our knowledge, this is the first demonstration that TorsinA protects against oxidative stress. We speculate that a loss of this cellular function in mutant TorsinA may be linked to the pathogenesis of early-onset dystonia...

..Fibromyalgia syndrome (FMS) patients and their doctors frequently complain on interaction difficulties. We investigated the effects of a shared decision-making (SDM) intervention on physician-patient interaction and health outcome...