Antagonists of adenosine A2A receptors as a new therapy of Parkinson’s disease

Parkinson's disease (PD) is a devastating neurodegenera-tive disorder with not completely understood etiology. In its pathomechanism degeneration of dopamine (DA) cell bodies in substantia nigra pars compacta correlate with appearance of Lewy bodies in histological investigation. Cardinal motor symptoms of PD such as akinesia, rigidity and tremor are reduced by administration of L-DOPA in combination with a peripheral decarboxylase inhibitor which is " a gold standard " in treatment of PD. However, complications such as refractory fluctuations, dyskinesias and tolerance develop after long-term L-DOPA therapy. In addition, L-DOPA is neurotoxic for remaining DA neu-rons due to free radicals generation after it is converted into DA. In the last years adenosine A2A receptor antagonists emerged as a new non-dopaminergic therapy of PD. Aden-osine A2A antagonists were shown to alleviate symptoms of PD in a number of behavioral studies in rodents and primates. In rodent models of PD they increased locomo-tor activity in MPTP-treated or reserpinized mice, reversed haloperidol-induced catalepsy in rats and potentiated ro-tational behavior produced by L-DOPA in 6-OHDA-le-sioned rats. In primates treated with MPTP, adenosine A2A antagonists increased motor activity and decreased dyski-nesia induced by a prolonged administration of L-DOPA. The mechanism of antiparkinsonian effects of A2A antagonists is based on their ability to modulate GABA release and to decrease DA-dependent activation of the indirect striatopallidal pathway. Presynaptically, A2A antagonists potentiate D2 receptor control of glutamatergic transmission. Recently, a neuroprotective potential of adenosine A2A receptor antagonists has been suggested. The protective effects of A2A receptor antagonists as well as caffeine was observed in an animal MPTP neurotoxicity model or in ischemia and excitotoxicity brain injury models. Oxida-tive stress is regarded as the main factor contributing to the etiology o PD. Overactive glutamatergic transmission resulting from disturbed DA-glutamate balance and a decreased vesicular monoamine transporter (VMAT2) function which leads to the disruption of DA sequestration are important factors in generation of oxidative stress in PD. Moreover, progressive degeneration of DA neurons is associated with chronic neuroinflammation and microglia activation triggering free radicals production. It was found that in 6-OHDA-model of PD, A2A adenosine receptor antagonists administered in combination with L-DOPA restored DA-glutamate balance and suppressed overproduction of hydroxyl radical. They also decreased hydroxyl radical level in inflammatory model. However, under condition of disturbed VMAT2 function in an early PD, A2A antagonists, particularly bearing properties of MAO-B in-hibitor, may cause risk of oxidative stress resulting from dysfunctional storage mechanism.