Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous l -DOPA delivery in the 6-OHDA model of Parkinson's disease

Mulas, Giovanna; Espa, Elena; Fenu, Sandro; Spiga, Saturnino; Cossu, Giovanni; Pillai, Elisabetta; Carboni, Ezio; Simbula, Gabriella; Jadžić, Dragana; Angius, Fabrizio; Spolitu, Stefano; Batetta, Barbara; Lecca, Daniele; Giuffrida, Andrea; Carta, Anna R.

doi:10.1016/j.expneurol.2016.09.013

Cited by 88 publications

(134 citation statements)

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“…In comparing animal and human studies, it is important to consider any differences in drug testing procedures, study design, and study populations between preclinical investigations and clinical trials. For example, animal models of LID are based on “clean” nigrostriatal lesions, and one can never exclude that additional components of the PD pathology (eg, neuroinflammation) or other pathologies may make dyskinesia more resistant to pharmacological modulation in patients. Other differences pertain to the heterogeneity of the PD population in terms of clinicopathological subtypes and previous drug exposure, factors that are likely to play a role in the response to putative antidyskinetic drugs.…”

Section: Construct Validity and Predictive Validity Of Rodent Models mentioning

confidence: 99%

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Animal models of l‐dopa‐induced dyskinesia in Parkinson's disease

Cenci

Crossman

2018

Movement Disorders

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Understanding the biological mechanisms of l-dopa-induced motor complications is dependent on our ability to investigate these phenomena in animal models of Parkinson's disease. The most common motor complications consist in wearing-off fluctuations and abnormal involuntary movements appearing when plasma levels of l-dopa are high, commonly referred to as peak-dose l-dopa-induced dyskinesia. Parkinsonian models exhibiting these features have been well-characterized in both rodent and nonhuman primate species. The first animal models of peak-dose l-dopa-induced dyskinesia were produced in monkeys lesioned with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated chronically with l-dopa to elicit choreic movements and dystonic postures. Seminal studies were performed in these models using both metabolic mapping and electrophysiological techniques, providing fundamental pathophysiological insights that have stood the test of time. A decade later, it was shown possible to reproduce peak-dose l-dopa-induced dyskinesia in rats and mice rendered parkinsonian with nigrostriatal 6-hydroxydopamine lesions. When treated with l-dopa, these animals exhibit abnormal involuntary movements having both hyperkinetic and dystonic components. These models have enabled molecular- and cellular-level investigations into the mechanisms of l-dopa-induced dyskinesia. A flourishing literature using genetically engineered mice is now unraveling the role of specific genes and neural circuits in the development of l-dopa-induced motor complications. Both non-human primate and rodent models of peak-dose l-dopa-induced dyskinesia have excellent construct validity and provide valuable tools for discovering therapeutic targets and evaluating potential treatments. © 2018 International Parkinson and Movement Disorder Society.

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Section: Construct Validity and Predictive Validity Of Rodent Models mentioning

confidence: 99%

“…L-dopa is, however, more effective than DA agonists in ameliorating the cardinal motor features of PD. 8 In addition, the pulsatile method of drug delivery has a significant part to play because motor fluctuations 9 and perhaps also dyskinesias 10,11 are ameliorated by continuous dopaminergic stimulation (eg, intrajejeunal L-dopa infusion).…”

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confidence: 99%

Animal models of l‐dopa‐induced dyskinesia in Parkinson's disease

Cenci

Crossman

2018

Movement Disorders

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“…Thus, l -DOPA treatment likely induces a shorter duration of dopaminergic stimulation in these mice. This condition is known to induce severe dyskinesia (Papathanou et al, 2011; Mulas et al, 2016). On the other hand, continuous l -DOPA administration reduces LID in Parkinson's patients (Timpka et al, 2016) and prolongs the half-life of l -DOPA via COMT inhibition to decrease dyskinesia (Espinoza et al, 2012; Müller, 2015).…”

Section: Discussionmentioning

confidence: 99%

Human COMT over-expression confers a heightened susceptibility to dyskinesia in mice

Solís

García-Montes

García‐Sanz

et al. 2017

Neurobiology of Disease

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Catechol-O-methyltransferase (COMT) degrades dopamine and its precursor L-DOPA and plays a critical role in regulating synaptic dopamine actions. We investigated the effects of heightened levels of COMT on dopamine-regulated motor behaviors and molecular alterations in a mouse model of dyskinesia. Transgenic mice overexpressing human COMT (TG) and their wildtype (WT) littermates received unilateral 6-OHDA lesions in the dorsal striatum and were treated chronically with L-DOPA for two weeks. L-DOPA-induced dyskinesia was exacerbated in TG mice without altering L-DOPA motor efficacy as determined by contralateral rotations or motor coordination. Inductions of FosB and phospho-acetylated histone 3 (molecular correlates of dyskinesia) were potentiated in the lesioned striatum of TG mice compared with their WT littermates. The TG mice had lower basal levels of dopamine in the striatum. In mice with lesions, L-DOPA induces a greater increase in the dopamine metabolite 3-methoxytyramine in the lesioned striatum of dyskinetic TG mice than in WT mice. The levels of serotonin and its metabolite were similar in TG and WT mice. Our results demonstrate that human COMT overexpression confers a heightened susceptibility to L-DOPA-induced dyskinesia and alters molecular and neurochemical responses in the lesioned striatum of mice.

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“…Although the field has necessarily focused on such processes to identify novel biomarkers and neuroprotective strategies for Parkinson's disease, an accumulating number of studies have suggested that a proinflammatory milieu may also underlie LID. For example, chronic l ‐dopa treatment increases neuroinflammatory markers in the basal ganglia of preclinical models of Parkinson's disease, immunomodulatory strategies have been reported to reduce the development and/or expression of LID, and mechanistically, neuroinflammatory factors can directly or indirectly influence prodyskinetic synaptic plasticity and angiogenesis …”

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confidence: 99%

“…For example, chronic L-dopa treatment increases neuroinflammatory markers in the basal ganglia of preclinical models of Parkinson's disease, immunomodulatory strategies have been reported to reduce the development and/or expression of LID, and mechanistically, neuroinflammatory factors can directly or indirectly influence prodyskinetic synaptic plasticity and angiogenesis. [5][6][7][8][9] Boi and colleagues capitalize on prior suggestions that the proinflammatory cytokine tumor necrosis factor α (TNF-α) may play a pivotal role in LID by investigating the effects of 2 blood-brain barrier-permeable TNF-α inhibitors, the Food and Drug Administration-approved compound thalidomide (TLD) and its more selective and potent derivative, 3,6 0 -dithiothalidomide (DTT) in the well-established unilateral 6-hydroxydopamine rat model of Parkinson's disease and LID. 10 Their overarching hypothesis was that both TNF-α inhibitors would attenuate LID via their known immunomodulatory actions and thus implicate such drugs for clinical translation.…”

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confidence: 99%

Neuroinflammation: Fanning the fire of l‐dopa‐induced dyskinesia

Bishop

2019

Movement Disorders

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Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous l -DOPA delivery in the 6-OHDA model of Parkinson's disease

Cited by 88 publications

References 50 publications

Animal models of l‐dopa‐induced dyskinesia in Parkinson's disease

Animal models of l‐dopa‐induced dyskinesia in Parkinson's disease

Human COMT over-expression confers a heightened susceptibility to dyskinesia in mice

Neuroinflammation: Fanning the fire of l‐dopa‐induced dyskinesia

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