L-Dopa induced dyskinesias in Parkinsonian mice: disease severity or L-Dopa history
| Autor: | Oscar Diaz, Lufei Shan, Barry J. Hoffer, Bruce Ladenheim, YaJun Zhang, Yung Hsiao Chiang, Lars Olson, Cristina M. Bäckman, Jean Lud Cadet |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Dyskinesia Drug-Induced Time Factors Neuroscience(all) Dopamine Clinical Neurology Nigrostriatal function Striatum Severity of Illness Index Sensitization Article MitoPark mouse Levodopa Benserazide Mice Internal medicine Basal ganglia medicine Animals Antidiarrheals Molecular Biology Denervation Behavior General Neuroscience Glutamate receptor Parkinson Disease Motor complication Abnormal involuntary movement Corpus Striatum nervous system diseases Receptors Neurotransmitter Disease Models Animal Endocrinology Dyskinesia Neurology (clinical) Serotonin medicine.symptom Psychology Neuroscience Locomotion Developmental Biology medicine.drug |
| Popis: | In Parkinson’s disease, the efficacy of l-Dopa treatment changes over time, as dyskinesias emerge with previously beneficial doses. Using MitoPark mice, that models mitochondrial failure in dopamine (DA) neurons and mimics the progressive loss of dopamine observed in Parkinson’s disease, we found that the severity of DA denervation and associated adaptations in striatal neurotransmission at the time of initiation of l-Dopa treatment determines development of l-Dopa induced dyskinesias. We treated 20-week, and 28-week old MitoPark mice with l-Dopa (10mg/kg i.p. twice a day) and found locomotor responses to be significantly different. While all MitoPark mice developed sensitization to l-Dopa treatment over time, 28-week old MitoPark mice with extensive striatal DA denervation developed abnormal involuntary movements rapidly and severely after starting l-Dopa treatment, as compared to a more gradual escalation of movements in 20-week old animals that started treatment at earlier stages of degeneration. Our data support that it is the extent of loss of DA innervation that determines how soon motor complications develop with l-Dopa treatment. Gene array studies of striatal neurotransmitter receptors revealed changes in mRNA expression levels for DA, serotonin, glutamate and GABA receptors in striatum of 28-week old MitoPark mice. Our results support that delaying l-Dopa treatment until Parkinson’s disease symptoms become more severe does not delay the development of l-Dopa-induced dyskinesias. MitoPark mice model genetic alterations known to impair mitochondrial function in a subgroup of Parkinson patients and provide a platform in which to study treatments to minimize the development of dyskinesia. |
| Databáze: | OpenAIRE |
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