TY - JOUR
T1 - Protection of midbrain dopaminergic neurons by the end-product of purine metabolism uric acid: Potentiation by low-level depolarization
AU - Guerreiro, Serge
AU - Ponceau, Aurélie
AU - Toulorge, Damien
AU - Martin, Elodie
AU - Alvarez-Fischer, Daniel
AU - Hirsch, Etienne C.
AU - Michel, Patrick P.
PY - 2009/5/1
Y1 - 2009/5/1
N2 - 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 H2O2 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 Ca2+ 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.
AB - 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 H2O2 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 Ca2+ 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.
UR - http://www.scopus.com/inward/record.url?scp=65649126049&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2009.06040.x
DO - 10.1111/j.1471-4159.2009.06040.x
M3 - Journal articles
C2 - 19302482
AN - SCOPUS:65649126049
SN - 0022-3042
VL - 109
SP - 1118
EP - 1128
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 4
ER -