Protective effects of riluzole on dopamine neurons: involvement of oxidative stress and cellular energy metabolism.
Riluzole is neuroprotective in patients with amyotrophic lateral sclerosis and may also protect dopamine (DA) neurons in Parkinson's disease. We examined the neuroprotective potential of riluzole on DA neurons using primary rat mesencephalic cultures and human dopaminergic neuroblastoma SH-SY5Y cells. Riluzole (up to 10 microM:) alone affected neither the survival of DA neurons in primary cultures nor the growth of SH-SY5Y cells after up to 72 h. Riluzole (1-10 microM:) dose-dependently reduced DA cell loss caused by exposure to MPP(+) in both types of cultures. These protective effects were accompanied by a dose-dependent decrease of intracellular ATP depletion caused by MPP(+) (30-300 microM:) in SH-SY5Y cells without affecting intracellular net NADH content, suggesting a reduction of cellular ATP consumption rather than normalization of mitochondrial ATP production. Riluzole (1-10 microM:) also attenuated oxidative injury in both cell types induced by exposure to L-DOPA and 6-hydroxydopamine, respectively. Consistent with its antioxidative effects, riluzole reduced lipid peroxidation induced by Fe(3+) and L-DOPA in primary mesencephalic cultures. Riluzole (10 microM) did not alter high-affinity uptake of either DA or MPP(+). However, in the same cell systems, riluzole induced neuronal and glial cell death with concentrations higher than those needed for maximal protective effects (> or =100 microM:). These data demonstrate that riluzole has protective effects on DA neurons in vitro against neuronal injuries induced by (a) impairment of cellular energy metabolism and/or (b) oxidative stress. These results provide further impetus to explore the neuroprotective potential of riluzole in Parkinson's disease.
Storch
A
A
Department of Neurology, University of Ulm Medical School, Ulm, Germany. alexander.storch@medizin.uni-ulm.de
Burkhardt
K
K
Ludolph
A C
AC
Schwarz
J
J
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides; D004298:Dopamine / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D005290:Ferric Compounds / Q000494:pharmacology; D006801:Humans; D007980:Levodopa / Q000037:antagonists & inhibitors / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D019782:Riluzole / Q000494:pharmacology*
D002712:Chlorides; D005290:Ferric Compounds; D007980:Levodopa; D019782:Riluzole; D016627:Oxidopamine; D000255:Adenosine Triphosphate; D015655:1-Methyl-4-phenylpyridinium; C024555:ferric chloride; D004298:Dopamine