title: Clinical/pharmacological aspect of adenosine A2A receptor antagonist for dyskinesia.
abstract: Dopamine replacement therapy using the dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), with a peripheral dopa decarboxylase inhibitor is the most effective treatment currently available for the symptoms of Parkinson's disease (PD). However, the long-term use of dopaminergic therapies for PD is often limited by the development of motor response complications, such as dyskinesia. Adenosine A2A receptors are a promising nondopaminergic target for the treatment of PD. The treatment of motor response complications involves combinations of regular and controlled release L-DOPA, perhaps with the addition of a COMT inhibitor or the use of a longer-acting dopamine agonist. However, when dyskinesia is already established, the increase in dopaminergic load produced by the addition of a dopamine agonist can result in an increase in the severity and duration of dyskinesia. Currently, there are no well-tolerated antidyskinesia agents available. Amantadine, which may exert its effects through the inhibition of N-methyl-D-aspartate (NMDA) receptors, shows some effects on established dyskinesia. Dyskinesia has a negative impact on the quality of life of patients, sometimes being more disabling than PD itself. Although some patients prefer experiencing dyskinesia than being in the OFF state and unable to move, alternative, more effective therapies are still required for severe disabling dyskinesia to afford patients an improved quality of life while in the ON state. The mechanisms causing and maintaining the dyskinesia have not been clarified. The application of a nondopaminergic approach to modify the basal ganglial activity would be helpful to better understand and treat dyskinesia. The use of an adenosine A2A receptor may provide one such approach. In this literature review, we will summarize the current knowledge from both clinical and nonclinical studies on the effects of adenosine A2A receptor blockade on dyskinesia.
authors.affiliation: Central Nervous System R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan. Electronic address: tomoyuki.kanda@kyowa-kirin.co.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kanda
authors.affiliation: Central Nervous System R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Uchida
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents
keywords: Adenosine A(2A) receptor; Antagonist; Dyskinesia; Istradefylline; Parkinson's disease; l-DOPA