Neuroprotection by adenosine A_2A receptor blockade in experimental models of Parkinson's disease

Abstract

Adenosine A 2A receptors are abundant in the caudate-putamen and involved in the motor control in several species. In MPTP-treated monkeys, A 2A receptor-blockade with an antagonist alleviates parkinsonian symptoms without provoking dyskinesia, suggesting this receptor may offer a new target for the antisymptomatic therapy of Parkinson's disease. In the present study, a signi®cant neuroprotective effect of A 2A receptor antagonists is shown in experimental models of Parkinson's disease. Oral administration of A 2A receptor antagonists protected against the loss of nigral dopaminergic neuronal cells induced by 6-hydroxydopamine in rats. A 2A antagonists also prevented the functional loss of dopaminergic nerve terminals in the striatum and the ensuing gliosis caused by MPTP in mice. The neuroprotective property of A 2A receptor antagonists may be exerted by altering the packaging of these neurotoxins into vesicles, thus reducing their effective intracellular concentration. We therefore conclude that the adenosine A 2A receptor may provide a novel target for the long-term medication of Parkinson's disease, because blockade of this receptor exerts both acutely antisymptomatic and chronically neuroprotective activities.

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

“…The longterm utility of Trk antagonists may be limited by their effects on the maintenance of neuromuscular junction integrity (Gonzalez et al, 1999) and learning and memory (Korte et al, 1996;Messaoudi et al, 2002;Pang et al, 2004). Adenosine A2a receptor antagonists have been shown to be neuroprotective agents in animal models of parkinsonism (Shiozaki et al, 1999;Koga et al, 2000;Ikeda et al, 2002;Fink et al, 2004). Potential adverse effects on inflammation (Ohta and Sitkovsky, 2001;Thiel et al, 2005) and coronary artery vasoregulation (Belardinelli et al, 1998) have not limited their safe use in humans with Parkinson's disease (Bara-Jimenez et al, 2003;Kase et al, 2003).…”

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…This emphasises again that the Fabnormal_ high density of A 2A Rs in striatal medium spiny neurons of the indirect pathway fulfils a very particular role in the control of striatal circuitry and that our knowledge about striatal A 2A Rs should not be extrapolate to understand the general role of A 2A Rs in the brain. Nevertheless, although A 2A R blockade is particularly effective in preventing cortical and hippocampal damage [225, 229, 231Y237], it is also effective in attenuating striatal damage following brain ischemia [229,231], exposure to quinolinic acid [230,238], 3-nitropropionic acid [239,240], malonate [241] or MPTP [242,243].…”

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

“…Adenosine has been proposed as an endogenous neuroprotective agent in ischemia, stroke, epilepsy, Alzheimer's disease, and Parkinson's disease [13,32,53,61]. Adenosine receptor agonists have been reported to protect against ischemic cell death in vivo [2,11,14,66] and in vitro [22].…”

“…However, caffeine and adenosine A 2A receptor antagonists block β-amyloidinduced neurotoxicity in rat cultured cerebellar granule neurons [13]. Furthermore, in an animal model of Parkinson's disease, administration of A 2A receptor antagonists protected against the loss of nigral dopaminergic neuronal cells induced by 6-hydroxydopamine in rats and prevented the functional loss of dopaminergic nerve terminals in the striatum and the ensuing gliosis caused by MPTP in mice [32] Protein phosphorylation is one the most important signaling mechanisms regulating cellular function. Phosphorylation is a dynamic process, involving shifting activities of kinases and phosphatases in the cell.…”