ORAL <i>L</i>‐DOPA TREATMENT OF PARKINSONISM

Andén, Nils‐Erik; Carlsson, Arvid; Kerstell, J; Magnusson, Tomas; Olsson, Rolf; Roos, B. E.; Steen, Bertil; Steg, Göran; Svanborg, Alvar; Thieme, Georg; Werdinius, Bengt

doi:10.1111/j.0954-6820.1970.tb02939.x

Cited by 65 publications

(11 citation statements)

References 10 publications

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“…When such lesioned animals are treated with DA receptor agonists, animals rotate contralaterally, away from the side of the lesion. This robust behavioural paradigm still serves, some 30 years since its introduction, as the standard for determining the effect of DA depletion in the striatum (Anden et al, 1970). In this model, administration of a so-called “priming” dose of a DA receptor agonist sensitizes the animal to the effect of a subsequent challenge with DA agonists.…”

Section: Current Concept(s) Of Primingmentioning

confidence: 99%

Priming for l-dopa-induced dyskinesia in Parkinson’s disease: A feature inherent to the treatment or the disease?

Nadjar

Gerfen

Bézard

2009

Progress in Neurobiology

119

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Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson’s disease ultimately experienced by the vast majority of patients. This article does not review the increased understanding of dyskinesia pathophysiology we have seen during the past few years but, instead, specifically focuses upon the very first molecular events thought to be responsible for the establishment of dyskinesia and generally grouped under the term of “priming”. Priming is classically defined as the process by which the brain becomes sensitized such that administration of a dopaminergic therapy modifies the response to subsequent dopaminergic treatments. In this way, over time, with repeated treatment, the chance of dopaminergic stimulation eliciting dyskinesia is increased and once dyskinesia has been established, the severity of dyskinesia increases. In this opinion review, however, we aim at strongly opposing the common view of priming. We propose, and hopefully will demonstrate, that priming does not exist per se but is the direct and intrinsic consequence of the loss of dopamine innervation of the striatum (and other target structures), meaning that the first injections of dopaminergic drugs only exacerbate those mechanisms (sensitization) but do not induce them. Chronicity and pulsatility of subsequent dopaminergic treatment only exacerbates the likelihood of developing dyskinesia.

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Section: Current Concept(s) Of Primingmentioning

confidence: 99%

Priming for l-dopa-induced dyskinesia in Parkinson’s disease: A feature inherent to the treatment or the disease?

Nadjar

Gerfen

Bézard

2009

Progress in Neurobiology

119

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“…Over time, most PD patients develop involuntary movements, known as l -DOPA-induced dyskinesia (LID) (Anden et al, 1970) which impair even rudimentary motor tasks (Ahlskog and Muenter, 2001). …”

Section: Introductionmentioning

confidence: 99%

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Thiele

Chen

et al. 2014

Neurobiology of Disease

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Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the direct pathway becoming over-active. Here, we define synaptic plasticity abnormalities in these pathways associated with parkinsonism, symptomatic benefits of l-DOPA, and LID. We applied spike-timing dependent plasticity protocols to corticostriatal synapses in slices from 6-OHDA-lesioned mouse models of parkinsonism and LID, generated in BAC transgenic mice with eGFP targeting the direct or indirect output pathways, with and without l-DOPA present. In naïve mice, bidirectional synaptic plasticity, i.e. LTP and LTD, was induced, resulting in an EPSP amplitude change of approximately 50% in each direction in both striatal output pathways, as shown previously. In parkinsonism and dyskinesia, both pathways exhibited unidirectional plasticity, irrespective of stimulation paradigm. In parkinsonian animals, the indirect pathway only exhibited LTP (LTP protocol: 143.5 ± 14.6%; LTD protocol 177.7 ± 22.3% of baseline), whereas the direct pathway only showed LTD (LTP protocol: 74.3 ± 4.0% and LTD protocol: 63.3 ± 8.7%). A symptomatic dose of l-DOPA restored bidirectional plasticity on both pathways to levels comparable to naïve animals (Indirect pathway: LTP protocol: 124.4± 22.0% and LTD protocol: 52.1± 18.5% of baseline. Direct pathway: LTP protocol: 140.7 ± 7.3% and LTD protocol: 58.4 ± 6.0% of baseline). In dyskinesia, in the presence of l-DOPA, the indirect pathway exhibited only LTD (LTP protocol: 68.9 ± 21.3% and LTD protocol 52.0 ± 14.2% of baseline), whereas in the direct pathway, only LTP could be induced (LTP protocol: 156.6 ± 13.2% and LTD protocol 166.7 ± 15.8% of baseline). We conclude that normal motor control requires bidirectional plasticity of both striatal outputs, which underlies the symptomatic benefits of l-DOPA. Switching from bidirectional to unidirectional plasticity drives global changes in striatal pathway excitability, and underpins parkinsonism and dyskinesia.

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“…(52–71) Most pharmaceutical approaches focus on augmentation of the diminished neurotransmitter, dopamine, by either increasing production, extending half-life and/or decreasing metabolism. Dopamine is normally synthesized from the amino acid tyrosine in a series of enzymatic reactions initiated by the conversion of tyrosine to L-dopa by tyrosine hydroxylase and its co-factor tetrahydrobiopterin.…”

Section: Rationale For Gene Therapeutic Approachesmentioning

confidence: 99%

“…Introduced more than 40 years ago, this treatment effectively quells the motoric symptoms of akinesia and bradykinesia. (52) However, many patients gradually develop levodopa-induced dyskinesias and motor fluctuations about 5–15 years after the initiation of L-dopa treatment. (72, 73) The severity of the dyskinesias varies between patients and ongoing research efforts are focused on the development of new and more effective anti-dyskinetic medications.…”

Section: Rationale For Gene Therapeutic Approachesmentioning

confidence: 99%

Gene Therapy in Parkinsonʼs Disease

Feng

Maguire‐Zeiss

2010

CNS Drugs

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Neurodegenerative diseases pose a unique treatment challenge to clinicians due to the slow progression of disease, the profound neuron loss prior to clinical symptoms and the paucity of early diagnostic biomarkers and restorative therapies. Treatment options are further constrained by the post-mitotic nature of CNS neurons and restricted ability of these cells to regenerate. Lastly, because the blood brain barrier impedes peripheral access to the brain there are inherent limitations with respect to treatment especially protein and peptide-based therapeutics. Due to these intrinsic constraints, researchers are continuing to expand a therapeutic platform based on the delivery of genes engineered for efficient CNS expression. Gene therapeutic approaches were first tested almost 20 years ago and continue to evolve as a viable treatment for CNS neurodegenerative disorders. In this review we consider the current advances in human gene therapy for one common neurodegenerative disorder, Parkinson’s disease (PD).

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ORAL L‐DOPA TREATMENT OF PARKINSONISM

Cited by 65 publications

References 10 publications

Priming for l-dopa-induced dyskinesia in Parkinson’s disease: A feature inherent to the treatment or the disease?

Priming for l-dopa-induced dyskinesia in Parkinson’s disease: A feature inherent to the treatment or the disease?

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Gene Therapy in Parkinsonʼs Disease

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