Toxic effects of L-DOPA on mesencephalic cell cultures: protection with antioxidants

Pardo, Beatriz; Mena, María A.; Casarejos, Marı́a José; Paı́no, Carlos Luis; Yébenes, Justo Garcı́a de

doi:10.1016/0006-8993(95)00341-m

Cited by 123 publications

(78 citation statements)

References 47 publications

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“…These results contrast with previous studies using embryonic neurons cultured without an astrocyte layer, where L-DOPA is toxic at relatively low levels (Mena et al, 1993;Mytilineou et al, 1993;Pardo et al, 1995). In a previous study, we found that glia-conditioned medium protects against this toxicity (Mena et al, 1996).…”

Section: Effect Of L-dopa On Glutathione Levelscontrasting

confidence: 99%

“…However, neurons can maintain an intracellular glutathione poo1 by taking up cysteine provided by glial cells (Sagara et al, 1993). Protection from oxidation enhances the survival of mesencephalic cultures (Mena et al, 1993(Mena et al, , 1996Pardo et al, 1995), and the number of TH-positive neurons is increased if SOD, USH peroxidase, or L-NAC is added to the medium (Colton et al, 1995). We have shown that TH-positive neurons that overexpress SOD display increased neutite outgrowth and survival (Przedborski et al, 1996) and are protected from L-DOPA toxicity (Mena et al, 1997).…”

Section: Effect Of L-dopa On Glutathione Levelsmentioning

confidence: 90%

“…Although L-DOPA is toxic for catecholamine neurons in other in vitro systems (Melamed, 1986;Mena et aI., 1992Mena et aI., , 1993Pardo et al, 1995), catecholamines are required for the development of the nervous system and survival. Inactivation of the TH gene produced the death of 90% of mutant mice fetuses, whereas administration of L-DOPA to pregnant females resulted in complete rescue of mutant mice (Zhou et al, 1995).…”

Section: Effect Of L-dopa On Glutathione Levelsmentioning

confidence: 99%

“…Whereas relatively low levels (25 jiM) of L-DOPA are toxic in culture (Melamed, 1986;Mena et al, 1992Mena et al, , 1993Mytilineou et al, 1993;Pardo et al, 1995), the drug has not been seen to damage DA neurons in healthy animals (Hefti et al, 1981;Perry et al, 1984;Yurek et al, 1991;Blunt et al, 1993) or humans (Quinn et al, 1986). As L-DOPA is the most effective compound for symptomatic treatment of Parkinson' s disease (PD), its influence on the progression of the disease is particularly important.…”

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confidence: 99%

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Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Mena

Davila

Sulzer

1997

Journal of Neurochemistry

118

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L-DOPA IS toxic to catecholamine neurons in culture, but the toxicity is reduced by exposure to astrocytes. We tested the effect of L-DOPA on dopamine neurons using postnatal ventral midbrain neuron/cortical astrocyte cocultures in serum-free, glia-conditioned medium. L-DOPA (50 tiM) protected against dopamine neuronal cell death and increased the number and branching of dopamine processes. In contrast to embryonically derived glia-free cultures, where L-DOPA is toxic, postnatal midbrain cultures did not show toxicity at 200 1iM L-DOPA. The stereoisomer D-DOPA (50-400 btM) was not neurotrophic. The aromatic amino acid decarboxylase inhibitor carbidopa (25~zM) did not block the neurotrophic effect. These data suggest that the neurotrophic effect of L-DOPA is stereospecific but independent of the production of dopamine. However, L-DOPA increased the level of glutathione. Inhibition of glutathione peroxidase by Lbuthionine sulfoximine (3 1iM for 24 h) blocked the neurotrophic action of L-DOPA. N-Acetyl-L-cysteine (250 1iM for 48 h), which promotes glutathione synthesis, had a neurotrophic effect similar to that of L-DOPA. These data suggest that the neurotrophic effect of L-DOPA may be mediated, at least in part, by elevation of glutathione content. Key Words: L-DOPA-Glia-Glutathione-Parkinson's disease-Dopamine neurons.

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Section: Effect Of L-dopa On Glutathione Levelscontrasting

confidence: 99%

Section: Effect Of L-dopa On Glutathione Levelsmentioning

confidence: 90%

Section: Effect Of L-dopa On Glutathione Levelsmentioning

confidence: 99%

mentioning

confidence: 99%

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Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Mena

Davila

Sulzer

1997

Journal of Neurochemistry

118

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“…Neuronal Culture-Neuronal enriched cultures from embryonic Sprague-Dawley rat midbrain E-14 (crown rump, length 10 -12 mm) were obtained and prepared as described previously (39,40). The cells were seeded in Dulbecco's modified Eagle's medium with 15% fetal calf serum at a density of 10 5 cells/cm 2 in multiwells or glass cover slides previously coated with poly-D-lysine, 4.5 g/cm 2 , in 0.1 M borate buffer, pH 8.4.…”

Section: Methodsmentioning

confidence: 99%

Nitric Oxide Triggers the Toxicity due to Glutathione Depletion in Midbrain Cultures through 12-Lipoxygenase

Canals¹,

Casarejos

Bernardo

et al. 2003

Journal of Biological Chemistry

100

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Glutathione (GSH) depletion is the earliest biochemical alteration shown to date in brains ofHere we demonstrate that arachidonic acid (AA) metabolism through the 12-lipoxygenase (12-LOX) pathway is also central for this GSH-NO interaction. LOX inhibitors (nordihydroguaiaretic acid and baicalein), but not cyclooxygenase (indomethacin) or epoxygenase (clotrimazole) ones, prevent cell death in the culture, even when added 10 h after NO treatment. Furthermore, the addition of AA to GSH-depleted cultures precipitates a cell death process that is indistinguishable from that initiated by NO in its morphology, time course, and 12-LOX, GC, and PKG dependence. The first AA metabolite through the 12-LOX enzyme, 12-hydroperoxyeicosatetraenoic acid, induces cell death in the culture, and its toxicity is greatly enhanced by GSH depletion. In addition we show that if GSH synthesis inhibition persists for up to 4 days without any additional treatment, it will induce a cell death process that also depends on 12-LOX, GC, and PKG activation. In this study, therefore, we show that the signaling pathway AA/12-LOX/12-HPETE/GC/ PKG may be important in several pathologies in which GSH decrease has been documented, such as Parkinson's disease. The potentiating effect of NO over such a signaling pathway may be of relevance as part of the cascade of events leading to and sustaining nerve cell death.

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The vulnerability of nigral neurons to Parkinson's disease is unrelated to their intrinsic capacity for dopamine synthesis: Anin situ hybridization study

1999

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Toxic effects of L-DOPA on mesencephalic cell cultures: protection with antioxidants

Cited by 123 publications

References 47 publications

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Nitric Oxide Triggers the Toxicity due to Glutathione Depletion in Midbrain Cultures through 12-Lipoxygenase

The vulnerability of nigral neurons to Parkinson's disease is unrelated to their intrinsic capacity for dopamine synthesis: Anin situ hybridization study

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