Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease.
Adenosine A2A receptors are abundant in the caudate-putamen and involved in the motor control in several species. In MPTP-treated monkeys, A2A 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 significant neuroprotective effect of A2A receptor antagonists is shown in experimental models of Parkinson's disease. Oral administration of A2A receptor antagonists protected against the loss of nigral dopaminergic neuronal cells induced by 6-hydroxydopamine in rats. A2A 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 A2A 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 A2A 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.
Ikeda
Ken
K
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co, Ltd, Nagaizumi, Sunto, Shizuoka, Japan.
Kurokawa
Masako
M
Aoyama
Shiro
S
Kuwana
Yoshihisa
Y
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000493:pharmacokinetics; D015259:Dopamine Agents; D005911:Gliosis / Q000188:drug therapy / Q000517:prevention & control; D006540:Herbicides / Q000493:pharmacokinetics; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D013565:Sympatholytics; D014316:Tritium
D000970:Antineoplastic Agents; D015259:Dopamine Agents; D006540:Herbicides; D018696:Neuroprotective Agents; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D043705:Receptor, Adenosine A2A; D013565:Sympatholytics; D014316:Tritium; C111599:istradefylline; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine