PARKINSON’S DISEASE: NEW HOPE FOR LID
The currently available treatments for Parkinson’s disease (PD) are symptomatic, and do not alter the natural course of the disease, however the effectiveness of pharmacotherapy has greatly improved patients quality of life.
After its introduction in the early 1960s, oral dopamine replacement therapy quickly became the mainstay of treatment of the disorder. The first agent to be introduced was the dopamine precursor L-3,4-dihydroxyphenilalanine (L-DOPA), which was combined with peripheral blockers of dopa-decarboxylase (carbidopa or benserazide). The earliest treatment with the anticholinergic medications is still in use for tremor today, but their use is problematic because of severe side-effects. The most important alternatives to L-DOPA therapy are direct-acting dopamine receptor agonists, such as ropinirole, pramipexole, or pergolide, which have a mild neuroprotective effect and a longer half-life than L-DOPA and carbidopa. Unfortunately the side-effects of antagonists are similar to those of L-DOPA, including nausea, hallucinations and dyskinesias. Although also described for L-DOPA, recent studies have shown that daytime sedation with sudden “sleep attacks” is a significant side-effect of these compounds.
For all these reasons, L-DOPA-induced dyskinesia (LID) is on the focus of research.
Adenosine A2A receptor antagonists can reduce LID in patients suffering from PD. In a mouse model of PD, Xiao and his co-workers found that adenosine A2A receptor antagonists inhibited the development of symptoms of LID, and mice lacking forebrain A2A receptors showed reduced LID symptoms (Xiao D. et al. Forebrain adenosine A2A receptors contribute to L-3,4-dihydroxyphenylalanine-induced dyskynesia in hemiparkinsonian mice. J. Neurosci 26, 13548-13555, 2006).
Results described in Xiao’s paper provide evidence that adenosine A2A receptors contribute to LID and that they might be a novel pharmacological target.