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  • 1
    Electronic Resource
    Electronic Resource
    l-DOPA Up-Regulates Glutathione and Protects Mesencephalic Cultures Against Oxidative Stress (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Incubation with l-DOPA induced a rise in GSH level in cultures of fetal rat mesencephalon, mouse neuroblastoma (Neuro-2A), human neuroblastoma (SK-N-MC), pig kidney epithelial cells (LLC-PK1), and glia from newborn rat brain, but not C6 glioma cells or neuronal cultures (no glia) from the mesencephalon. The pure neuronal cultures were destroyed by incubation with l-DOPA; added ascorbic acid or superoxide dismutase protected the cells. Washout of l-DOPA after 48 h amplified the rise in GSH content in mixed cultures (neurons plus glia). Examination of structure-activity relationships for elevating GSH levels in responsive cell types revealed that autooxidizable compounds (α-methyl-DOPA, dopamine, apomorphine, catechol, and hydroquinone) behaved similarly to l-DOPA, whereas structural analogues that cannot undergo autooxidation (3-O-methyl-DOPA, tyrosine, 2,4-dihydroxyphenylalanine, and resorcinol) failed to elevate GSH levels. Therefore, up-regulation of GSH appears to be a response to a mild oxidative stress. When mixed mesencephalic cultures were exposed to a strong oxidant stress by incubation with tert-butyl hydroperoxide, a loss in viability was seen. Cultures pretreated with l-DOPA or hydroquinone were protected from loss of viability. However, when cultures were pretreated with both l-DOPA and ascorbate, which prevents the rise in GSH level, protection was lost, in accord with the failure to up-regulate GSH. These results show that the up-regulation of cellular GSH evoked by autooxidizable agents is associated with significant protection of cells. Glia play an essential role in the response of mesencephalic cell cultures. An ability to up-regulate GSH may serve a protective role in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66020501.x
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  • 2
    Electronic Resource
    Electronic Resource
    Glial Cell Line-Derived Neurotrophic Factor Exerts Neurotrophic Effects on Dopaminergic Neurons In Vitro and Promotes Their Survival and Regrowth After Damage by 1-Methyl-4-Phenylpyridinium (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The effect of glial cell line-derived neurotrophic factor (GDNF) on the growth of mesencephalic dopaminergic neurons and on their survival following exposure to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) was examined in vitro. In cultures developing under normal conditions, GDNF at 1 ng/ml optimally improved the survival and stimulated the growth of dopaminergic neurons without affecting glial growth. In cultures treated with MPP+, GDNF could not prevent toxicity to dopaminergic neurons. The uptake of [3H]dopamine and the number of tyrosine hydroxylase-positive neurons were similarly reduced by MPP+ in the presence or absence of GDNF. However, after removal of MPP+, GDNF protected dopaminergic neurons from the continuous cell death and stimulated the regrowth of dopaminergic fibers damaged by MPP+. We conclude that GDNF supports the growth of normally developing dopaminergic neurons and stimulates their survival and recovery after damage. These findings suggest that GDNF could be useful in the development of therapeutic approaches to Parkinson's disease, which is characterized by dopaminergic cell loss.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66010074.x
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  • 3
    Electronic Resource
    Electronic Resource
    Ascorbic Acid in Mesencephalic Cultures: Effects on Dopaminergic Neuron Development (1991)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 57 (1991), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Ascorbic acid exists in high intracellular concentrations in fetal rat brain. In mesencephalic cultures the cellular ascorbic acid content drops sharply to undetectable levels when no ascorbic acid is added to the medium, thus creating a model of scorbutic neuronal tissue and affording the study of ascorbic acid's effects on mesencephalic cell development and function. Cultures treated with 0.2 mM ascorbic acid were compared with controls (scorbutic cultures) by using morphological and biochemical indices. Ascorbic acid cultures at 7 and 14 days in vitro showed a marked increase in glial proliferation on glial fibrillary acidic protein staining and increased neurite growth and number on tyrosine hydroxylase staining. Significantly higher dopamine uptake and levels of dopamine and 3, 4-dihydroxyphenylacetic acid were also observed after 7 and 14 days of ascorbic acid treatment. The capacity to accumulate ascorbic acid and the ability to retain the intracellular ascorbic acid developed gradually as the cultures matured. Ascorbic acid reached the embryonal levels by day 14 in vitro. We conclude that although neuronal cultures can survive and grow in the absence of detectable levels of ascorbic acid, its presence exerts a broad effect on dopamine neuron morphology and biochemical functioning either directly or through increased glial proliferation, or possibly both.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1991.tb03773.x
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  • 4
    Electronic Resource
    Electronic Resource
    Studies on the Metabolism and Toxicity of l-Methyl-4-Phenyl-l,2,3,6-Tetrahydropyridine in Cultures of Embryonic Rat Mesencephalon (1988)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 51 (1988), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The metabolism of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied in dissociated cell cultures prepared from embryonic rat mesencephalon. MPTP was added to the feeding medium and at the end of the incubation period MPTP was separated from the water-soluble metabolite by ether extraction. Our results demonstrate that, in cultures, MPTP is oxidized predominantly by monoamine oxidase B, since deprenyl but not clorgyline had an inhibitory effect on its metabolism. The metabolite of MPTP diffuses freely in the feeding medium (99% of the total) and its concentration increases with time. The concentration of the metabolite can be increased by increasing the number of cells plated into the tissue culture dish and the toxicity to dopamine neurons depends on the amount of metabolite accumulated in the feeding medium. The metabolism of MPTP is reduced by decreasing the number of glial cells present in the cultures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1988.tb01809.x
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  • 5
    Electronic Resource
    Electronic Resource
    Deprenyl Protects Dopamine Neurons from the Neurotoxic Effect of 1-Methyl-4-Phenylpyridinium Ion (1985)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 45 (1985), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: 1-Methyl-4-phenylpyridinium ion (MPP+) is the product of the metabolic oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by mono-amine oxidase (MAO). MPP+ is toxic to 3,4-dihydroxy-phenylethylamine (dopamine, DA) neurons in explant cultures of rat embryonic midbrain. Addition of 2.5 μM MPP+ to the feeding medium for 6 days results in significant reduction of the DA levels in the cultures (to 19% of control) as well as in the uptake of [3H]DA (to 32% of control). When the cultures are treated with the MAO inhibitor deprenyl (10 μM) 24 h prior to and during exposure to MPP+, the DA neurons are protected from the toxicity of the drug. In the combined deprenyl plus MPP+ treatment, the levels of DA in the cultures remain at the control range and the [3H]DA uptake is reduced to only 73% of control. These results indicate that MAO is involved in the toxicity of MPP+ on DA neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1985.tb10556.x
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  • 6
    Electronic Resource
    Electronic Resource
    Toxic and Protective Effects of l-DOPA on Mesencephalic Cell Cultures (1993)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 61 (1993), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The autoxidation of L-DOPA or dopamine (DA) and the metabolism of DA by monoamine oxidase generate a spectrum of toxic species, namely, hydrogen peroxide, oxy radicals, semiquinones, and quinones. When primary dissociated cultures of rat mesencephalon were incubated with L-DOPA (200 μM) for 48 h, the number of tyrosine hydroxylase-positive neurons (DA neurons) was reduced to 69.7% of control values, accompanied by a decrease in [3H]DA uptake to 42.3% of control values; the remaining DA neurons exhibited reduced neurite length and overall deterioration. Lack of simultaneous change in the number of neurons stained with neuron-specific enolase indicated that toxicity was relatively specific for DA neurons. At the same time, the level of GSH, a major cellular antioxidant, rose to 125.2% of control values. Thus, exposure of mesencephalic cultures to L-DOPA results in both damaging and antioxidant actions. Ascorbate (200 μM), an antioxidant, prevented the rise in GSH. The effect of ascorbate on GSH points to an oxidative signal to initiate the rise in GSH content. On the other hand, neither inhibition of monoamine oxidase with pargyline nor addition of superoxide dismutase or catalase to the culture medium prevented the rise in GSH level or the loss in [3H]DA uptake. The latter results tend to exclude the products of monoamine oxidase activity or the presence of hydrogen peroxide or superoxide in the medium as responsible agents for the rise in GSH or neuronal toxicity. In cultures treated with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, l-DOPA prevented cell death by L-BSO.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1993.tb13642.x
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  • 7
    Electronic Resource
    Electronic Resource
    Mesencephalic Dopamine Neurons Become Less Sensitive to 1 -Methyl-4-Phenyl-l,2,3,6-Tetrahydropyridine Toxicity During Development In Vitro (1989)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 53 (1989), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The in vitro development of monoamine oxidase (MAO) activity and [3H]dopamine (DA) uptake capacity of dissociated cell cultures from rat embryo mesencephalon were correlated with the potency of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and l-methyl-4-phenylpyridine (MPP+) neurotoxicity. Specific activities of both MAO-A and MAO-B increased during in vitro development of the cultures, with MAO-B activity increasing 20-fold between the first and fourth week. Similarly, [3H]DA accumulation increased 2.6-fold between the first and third week in vitro, when it reached a plateau. Unexpectedly, the toxicities of MPTP and MPP+were substantially decreased in the older cultures. Exposure to MPTP reduced [3H]DA accumulation per culture by 77% in 1-week-old cultures and by 36% in 4-week-old cultures. Similarly, damage caused by MPP+ was reduced from 84% of control in the first week to 34% of control in the fourth week. The attenuation of neurotoxicity was not due to an increase in storage of MPP+ in the synaptic vesicles of DA neurons, nor to a change in the distribution of MPP+ between dopaminergic and other cellular components of the cultures. The damage to DA neurons caused by the mitochondrial toxin, rotenone, also showed a similar reduction in the older cultures. These observations coupled with an increase in lactate formation and glucose consumption during the in vitro development of the cultures suggest a shift toward increased glycolysis and decreased dependence on aerobic metabolism. This would render the cells more resistant to the inhibition of mitochondrial function by MPP+.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1989.tb07408.x
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  • 8
    Electronic Resource
    Electronic Resource
    l-(−)-Desmethylselegiline, a Metabolite of Selegiline [l-(−)-Deprenyl], Protects Mesencephalic Dopamine Neurons from Excitotoxicity In Vitro (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Selegiline [l-(−)-deprenyl], a monoamine oxidase B inhibitor, has been used in the treatment of Parkinson's disease as a putative neuroprotective agent. Selegiline is metabolized rapidly in the gastrointestinal tract and liver to desmethylselegiline (DMS) and methamphetamine. We have previously shown that selegiline protects dopamine neurons in mesencephalic cultures from toxicity resulting from activation of glutamate receptors. In the present study we examined whether DMS has similar neuroprotective effects. Our data show that DMS protects dopamine neurons from N-methyl-d-aspartate receptor-mediated excitotoxic damage. The efficacy of DMS is greater than that of selegiline, as it can cause protection at lower concentrations and provide significantly greater levels of protection at the same concentrations. Our results suggest that DMS might be the active compound responsible for the neuroprotective properties of selegiline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68010434.x
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  • 9
    Electronic Resource
    Electronic Resource
    l-Deprenyl Protects Mesencephalic Dopamine Neurons from Glutamate Receptor-Mediated Toxicity In Vitro (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: l-Deprenyl is a relatively selective inhibitor of monoamine oxidase (MAO)-B that delays the emergence of disability and the progression of signs and symptoms of Parkinson's disease. Experimentally, deprenyl has also been shown to prevent neuronal cell death in various models through a mechanism that is independent of MAO-B inhibition. We examined the effect of deprenyl on cultured mesencephalic dopamine neurons subjected to daily changes of feeding medium, an experimental paradigm that causes neuronal death associated with activation of the NMDA subtype of glutamate receptors. Both deprenyl (0.5–50 µM) and the NMDA receptor blocker MK-801 (10 µM) protected dopamine neurons from damage caused by medium changes. The nonselective MAO inhibitor pargyline (0.5–50 µM) was not protective, indicating that protection by deprenyl was not due to MAO inhibition. Deprenyl (50 µM) also protected dopamine neurons from delayed neurotoxicity caused by exposure to NMDA. Because deprenyl had no inhibitory effect on NMDA receptor binding, it is likely that deprenyl protects from events occurring downstream from activation of glutamate receptors. As excitotoxic injury has been implicated in neurodegeneration, it is possible that deprenyl exerts its beneficial effects in Parkinson's disease by suppressing excitotoxic damage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68010033.x
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  • 10
    Electronic Resource
    Electronic Resource
    Glial Cells Mediate Toxicity in Glutathione-Depleted Mesencephalic Cultures (1999)
    Oxford UK : Blackwell Science Ltd
    Journal of neurochemistry 73 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We have examined the role of glial cells in the toxicity that results from inhibition of reduced glutathione (GSH) synthesis by L-buthionine sulfoximine (BSO) in mesencephalic cell cultures. We show that GSH depletion, to levels that cause total cell loss in cultures containing neurons and glial cells, has no effect on cell viability in enriched neuronal cultures. An increase in the plating cell density sensitizes glia-containing cultures to GSH depletion-induced toxicity. This suggests that cell death in this model is the consequence of events that are induced by GSH depletion and are mediated by glial cells. The antioxidant ascorbic acid and the lipoxygenase (LOX) inhibitor nordihydroguaiaretic acid (1-10 μM) provide full protection from BSO toxicity, indicating that arachidonic acid metabolism through the LOX pathway and the generation of reactive oxygen species play a role in the loss of cell viability. In contrast, inhibition of nitric oxide (NO) synthase affords only partial protection from BSO toxicity, suggesting that increased NO production cannot entirely account for cell death in this model. Our data provide evidence that GSH depletion in the presence of glial cells leads to neuronal degeneration that can be prevented by inhibition of LOX. This may have relevance to the pathogenesis of Parkinson’s disease, where glial activation and depletion of GSH have been found in the substantia nigra pars compacta.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0730112.x
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