Protection of midbrain dopaminergic neurons by the end-product of purine metabolism uric acid: potentiation by low-level depolarization.
High plasma levels of the end product of purine metabolism uric acid (UA) predict a reduced risk of developing Parkinson's disease suggesting that UA may operate as a protective factor for midbrain dopaminergic neurons. Consistent with this view, UA exerted partial but long-term protection in a culture model in which these neurons die spontaneously. The rescued neurons were functional as they accumulated dopamine, efficiently. The use of the fluorescent probe dihydrorhodamine-123 revealed that UA operated by an antioxidant mechanism. The iron chelating agent desferrioxamine, the H(2)O(2) scavenger enzyme catalase and the inhibitor of lipid peroxidation Trolox mimicked the effects of UA, suggesting that UA neutralized reactive oxygen species produced via a Fenton-type chemical reaction. UA was, however, not significantly accumulated into neurons, which indicates that the antioxidant effect occurred probably extracellularly. Structure - activity relationships among purine derivatives revealed that the antioxidant properties of UA resulted from the presence of a 8-one substituent in its chemical structure. Of interest, the stimulation of L-type Ca(2+) channels by high K(+)-induced depolarization and the ensuing activation of extracellular signal-regulated kinases 1/2 strongly improved the neuroprotective effect of UA whereas the depolarizing signal alone had no effect. In summary, our data indicate that UA may interfere directly with the disease's pathomechanism.
Guerreiro
Serge
S
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Paris 6, France.
Ponceau
Aurélie
A
Toulorge
Damien
D
Martin
Elodie
E
Alvarez-Fischer
Daniel
D
Hirsch
Etienne C
EC
Michel
Patrick P
PP
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D003600:Cytosol / Q000502:physiology; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D008636:Mesencephalon / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents; D018384:Oxidative Stress / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology; D011687:Purines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013936:Thymidine / Q000031:analogs & derivatives / Q000378:metabolism; D014527:Uric Acid / Q000031:analogs & derivatives / Q000494:pharmacology*
D018696:Neuroprotective Agents; D011687:Purines; D017382:Reactive Oxygen Species; D014527:Uric Acid; C012439:methylthymidine; D011188:Potassium; D002118:Calcium; D013936:Thymidine; D004298:Dopamine