Metabolic inhibition enhances selective toxicity of L-DOPA toward mesencephalic dopamine neurons in vitro.
Recent in vitro studies have described the toxicity of levodopa (L-DOPA) to dopamine (DA) neurons. We investigated whether metabolic inhibition with rotenone, an inhibitor of complex I of the mitochondrial respiratory chain, may enhance the toxicity of L-DOPA toward DA neurons in mesencephalic cultures. The uptakes of DA and GABA were determined to evaluate the functional and morphological integrity of DA and non-DA neurons, respectively. Pretreatment with rotenone significantly augmented the toxic effect of L-DOPA on DA neurons. Interestingly, prior metabolic inhibition with rotenone rendered DA cells susceptible to a dose (5 microM) of L-DOPA that otherwise exhibited no toxic effect. DA uptake was more intensely attenuated than GABA uptake after the combined exposure to rotenone and L-DOPA. This was confirmed by cell survival estimation showing that tyrosine hydroxylase-positive DA cells are more vulnerable to the sequential exposure to the drugs than total cells. The selective toxic effect of L-DOPA on rotenone-pretreated DA neurons was significantly blocked by antioxidants, but not antagonists of NMDA or non-NMDA glutamate receptors. This indicates that oxidative stress play a central role in mediating the selective damage of DA cells in the present experimental paradigm. Our results raise the possibility that long-term L-DOPA treatment could accelerate the progression of degeneration of DA neurons in patients with Parkinson's disease where potential energy failure due to mitochondrial defects has been demonstrated to take place.
Nakao
N
N
Department of Neurological Surgery, Wakayama Medical College, Japan.
Nakai
K
K
Itakura
T
T
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000633:toxicity*; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007980:Levodopa / Q000633:toxicity*; D008636:Mesencephalon / Q000166:cytology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D000975:Antioxidants; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D014475:Uncoupling Agents; D012402:Rotenone; D007980:Levodopa; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D016660:NAD(P)H Dehydrogenase (Quinone); D004298:Dopamine