Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons.
The neurotoxicity of L-DOPA and dopamine (DA) on striatal neurons was examined by using primary cultures of rat striatum. Exposure to L-DOPA and DA at concentrations of 30-300 microM induced dose-dependent cell death in both younger cultures (3 days in culture, 3 DIC) and elder cultures (10 days in culture, 10 DIC). The cytotoxicity of L-DOPA and DA was also dependent on the exposure time (6-24 h). Ascorbic acid (200 microM) inhibited both L-DOPA- and DA-induced cytotoxicity in 3 DIC cultures, whereas it provided significant protection against DA- but not L-DOPA-induced cytotoxicity in 10 DIC cultures. The L-DOPA cytotoxicity in 10 DIC cultures was prevented by a non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and by an NMDA receptor antagonist, MK-801. Neither antagonist prevented DA cytotoxicity. D-DOPA did not affect the viability of 10 DIC cultures, though it elicited marked toxicity in 3 DIC cultures. These results suggest that there are two components in the mechanisms that mediate the L-DOPA neurotoxicity on striatal neurons: one is autoxidation-relevant and the other is autoxidation-irrelevant. With respect to the latter, glutamate receptor stimulation may be involved. In contrast, autoxidation plays an important role in DA neurotoxicity.
Cheng
N
N
Department of Pharmacology, Faculty of Phannaceutical Sciences, Kyoto University, Japan.
Maeda
T
T
Kume
T
T
Kaneko
S
S
Kochiyama
H
H
Akaike
A
A
Goshima
Y
Y
Misu
Y
Y
D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001205:Ascorbic Acid / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D004298:Dopamine / Q000633:toxicity*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007980:Levodopa / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
D000978:Antiparkinson Agents; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D007980:Levodopa; D001205:Ascorbic Acid; D004298:Dopamine