Abstract
Long-term use of levodopa (l-dopa) is inevitably complicated with highly disabling fluctuations and drug-induced dyskinesias, which pose major challenges to the existing drug therapy of Parkinson's disease. In this study, we conducted a systematic review and meta-analysis to assess the efficacy of A2A receptor antagonists on reducing l-dopa-induced dyskinesias (LID). Nine studies with a total of 152 animals were included in this meta-analysis. Total abnormal involuntary movements (AIM) score, locomotor activity, and motor disability were reported as outcome measures in 5, 5, and 3 studies, respectively. Combined standardized mean difference (SMD) estimates were calculated using a random-effects model. We pooled the whole data and found that, when compared to l-dopa alone, A2A receptor antagonists plus l-dopa treatment showed no effect on locomotor activity (SMD -0.00, 95% confidence interval (CI): -2.52 to 2.52, p = 1.0), superiority in improvement of motor disability (SMD -5.06, 95% CI: -9.25 to -0.87, p = 0.02) and more effective in control of AIM (SMD -1.82, 95% CI: -3.38 to -0.25, p = 0.02). To sum up, these results demonstrated that A2A receptor antagonists appear to have efficacy in animal models of LID. However, large randomized clinical trials testing the effects of A2A receptor antagonists in LID patients are always warranted.
Highlights
Parkinson’s disease (PD) is defined by a set of motor signs and symptoms that are caused by selective degeneration of the dopamine (DA) neurons, which originate in the substantia nigra pars compacta and project into the striatum [1]
We have shown that adenosine A2A receptor antagonists are effective in the management of l-dopa-induced dyskinesias (LID) in animal models
The systematic review and meta-analysis here provides a framework for an evidence-based approach to the development of new treatments for LID and for the design of future preclinical and clinical studies
Summary
Parkinson’s disease (PD) is defined by a set of motor signs and symptoms that are caused by selective degeneration of the dopamine (DA) neurons, which originate in the substantia nigra pars compacta and project into the striatum [1]. The long-term use of l-dopa produces motor complications which include highly disabling fluctuations and l-dopa-induced dyskinesias (LID), representing the major challenges to the existing drug therapy of PD [3, 4]. Recent researches have revealed that a wide series of non-dopaminergic neurotransmitter systems (glutamatergic, serotoninergic, adrenergic, and cholinergic, etc.) are involved in pre- and postsynaptic changes and thereby contributing to the pathophysiology of LID [5] Based on such therapies, many drugs are available in the market to treat disabling LID, but potential side effects have limited their clinical use [7]. Long-term use of levodopa (l-dopa) is inevitably complicated with highly disabling fluctuations and drug-induced dyskinesias, which pose major challenges to the existing drug therapy of Parkinson’s disease
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