BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).
- MeSH
- antiparkinsonika * aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- aplikace orální MeSH
- chelátory železa * aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- deferipron * aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- dopaminové látky aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- dvojitá slepá metoda MeSH
- levodopa terapeutické užití MeSH
- lidé MeSH
- mozek - chemie MeSH
- mozek diagnostické zobrazování MeSH
- neutropenie chemicky indukované MeSH
- Parkinsonova nemoc * farmakoterapie metabolismus patofyziologie MeSH
- progrese nemoci MeSH
- substantia nigra * chemie diagnostické zobrazování účinky léků metabolismus MeSH
- železo * analýza metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
The oculomotor role of the basal ganglia has been supported by extensive evidence, although their role in scanning eye movements is poorly understood. Nineteen Parkinsońs disease patients, which underwent implantation of deep brain stimulation electrodes, were investigated with simultaneous intraoperative microelectrode recordings and single channel electrooculography in a scanning eye movement task by viewing a series of colored pictures selected from the International Affective Picture System. Four patients additionally underwent a visually guided saccade task. Microelectrode recordings were analyzed selectively from the subthalamic nucleus, substantia nigra pars reticulata and from the globus pallidus by the WaveClus program which allowed for detection and sorting of individual neurons. The relationship between neuronal firing rate and eye movements was studied by crosscorrelation analysis. Out of 183 neurons that were detected, 130 were found in the subthalamic nucleus, 30 in the substantia nigra and 23 in the globus pallidus. Twenty percent of the neurons in each of these structures showed eye movement-related activity. Neurons related to scanning eye movements were mostly unrelated to the visually guided saccades. We conclude that a relatively large number of basal ganglia neurons are involved in eye motion control. Surprisingly, neurons related to scanning eye movements differed from neurons activated during saccades suggesting functional specialization and segregation of both systems for eye movement control.
- MeSH
- antiparkinsonika terapeutické užití MeSH
- bazální ganglia účinky léků patofyziologie MeSH
- čtení MeSH
- dospělí MeSH
- globus pallidus účinky léků patofyziologie MeSH
- hluboká mozková stimulace MeSH
- implantované elektrody MeSH
- levodopa terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mapování mozku MeSH
- mikroelektrody MeSH
- neurony patologie MeSH
- nucleus subthalamicus účinky léků patofyziologie MeSH
- Parkinsonova nemoc farmakoterapie patofyziologie MeSH
- pohyby očí * MeSH
- rozpoznávání obrazu MeSH
- senioři MeSH
- substantia nigra účinky léků patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The use of the herbicide paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride; PQ) which is widely used in agriculture is known to cause dopaminergic neurotoxicity. However, the mechanisms underlying this effect are not fully understood. This present study investigated the behavioral manifestations, motor coordination, and dopaminergic neurodegeneration following exposure to PQ. Male rats were injected with PQ (10 mg/kg i.p.) daily for three weeks. Rotarod systems were used for measuring locomotor activity and motor coordination. The effects of PQ on dorsiflexor, electrophysiologically-induced muscle contraction were studied. Dopamine concentrations in the ventral mesencephalon were measured by high performance liquid chromatography and the number of dopaminergic neurons in substantia nigra pars compacta was estimated by tyrosine hydroxylase immunohistochemistry. PQ induced difficulty in movement and significant reduction in motor activity and twitch tension at the dorsiflexor skeletal muscle. The number of tyrosine hydroxylase positive neurons was significantly less in the substantia nigra pars compacta and nigral dopamine level was significantly reduced in PQ treated animals (20.4+/-3.4 pg/mg) when compared with control animals (55.0+/-2.4 pg/mg wet tissue). Daily treatment of PQ for three weeks induces selective dopaminergic neuronal loss in the substantia nigra and significant behavioral and peripheral motor deficit effects.
- MeSH
- ataxie chemicky indukované patofyziologie MeSH
- dopamin metabolismus MeSH
- down regulace účinky léků MeSH
- herbicidy otrava MeSH
- kosterní svaly účinky léků patofyziologie MeSH
- krysa rodu rattus MeSH
- nemoci svalů chemicky indukované patofyziologie MeSH
- neurotoxiny otrava MeSH
- paraquat otrava MeSH
- pohybová aktivita účinky léků MeSH
- potkani Wistar MeSH
- substantia nigra účinky léků metabolismus MeSH
- svalová síla účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antiparkinsonika škodlivé účinky MeSH
- dospělí MeSH
- finanční podpora výzkumu jako téma MeSH
- levodopa škodlivé účinky MeSH
- lidé MeSH
- parkinsonské poruchy farmakoterapie komplikace MeSH
- polékové dyskineze etiologie patologie MeSH
- substantia nigra patologie účinky léků zranění MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- MeSH
- elektrická stimulace MeSH
- epilepsie terapie MeSH
- GABA agonisté MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- nucleus subthalamicus MeSH
- receptory GABA MeSH
- substantia nigra anatomie a histologie fyziologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
- MeSH
- energetický metabolismus účinky léků MeSH
- flurothyl toxicita MeSH
- konvulziva toxicita MeSH
- krysa rodu rattus MeSH
- oxidy dusíku farmakologie MeSH
- status epilepticus farmakoterapie chemicky indukované metabolismus MeSH
- substantia nigra metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH