Protection from 1-methyl-4-phenylpyridinium (MPP+) toxicity and stimulation of regrowth of MPP+-damaged dopaminergic fibers by treatment of mesencephalic cultures with EGF and basic FGF

Park, Tina H.; Mytilineou, Catherine

doi:10.1016/0006-8993(92)90855-4

Cited by 91 publications

(46 citation statements)

References 66 publications

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“…the neurotoxin, such as glial cell line-derived neurotrophic factor (GDNF) (Hou et al, 1996), brain-derived neurotrophic factor (BDNF) (Hyman et al, 1991), epidermal growth factor, and basic fibroblast growth factor (Park and Mytilineou, 1992), do not mediate the protective effect of ara-C in the present model. This was confirmed for GDNF, with the use of a neutralizing monoclonal antibody mAb-2 12 (RD Systems) against recombinant human GDNF, which is also effective against the trophic factor from rat (C.…”

Section: Figmentioning

confidence: 61%

Rescue of Mesencephalic Dopamine Neurons by Anticancer Drug Cytosine Arabinoside

Michel

Ruberg

Agid

1997

Journal of Neurochemistry

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Nanomolar concentrations of cytosine arabinoside (ara-C), a structural analogue of 2 '-deoxycytidine (2'dC) used in the chemotherapy of cancer, proved to be highly effective in preventing the death of postmitotic dopaminergic neurons that occurs spontaneously by apoptosis in mesencephalic cultures. The rescued cells were totally functional and highly differentiated. The trophic/neuroprotective effects of ara-C were (1) specific for dopaminergic neurons; (2) long-lived, remaining detectable several days after withdrawal of the nucleoside analogue from the culture medium; (3) still observed when the treatment was delayed after plating; (4) abolished by an excess of 2'dC or dCTP, or by exposure to the neurotoxin 1-methyl-4-phenylpyridinium; and (5) mimicked by ara-CTP, 5-fluoro-2 '-deoxyuridine, and aphidicolin. Autoradiographic studies revealed that ara-C was incorporated exclusively into astrocyte nuclei, suggesting that the dopaminotrophic activity was indirect and resulted from the antiproliferative action of the modified nucleoside on glial cells at concentrations that were not neurotoxic. No evidence was found for putative deleterious or trophic molecules secreted by proliferating or ara-C-treated astrocytes, respectively, suggesting that neuroglial contact may play a role. Our results suggest a possible mechanism underlying neurodegeneration in Parkinson's disease, where selective loss of dopaminergic neurons in the mesencephalon is accompanied by astrogliosis.

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Section: Figmentioning

confidence: 61%

Rescue of Mesencephalic Dopamine Neurons by Anticancer Drug Cytosine Arabinoside

Michel

Ruberg

Agid

1997

Journal of Neurochemistry

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“…Furthermore, the neuro-protective and neurotrophic effects of bFGF in vitro are abolished by inhibition of cell proliferation, which implicates glia rather than neurons (Knüsel et al, 1990;Engele and Bohn, 1991;Park and Mytilineou, 1992;Hou et al, 1997). We have found that while bFGF enhances dopamine uptake, it does not improve the survival of dopaminergic neurons in vitro, nor is it able to protect them from MPP ϩ toxicity under culture conditions where cAMP was strongly protective (Hartikka et al, 1992).…”

Section: Discussionmentioning

confidence: 86%

L1 neural cell adhesion molecule is a survival factor for fetal dopaminergic neurons

1998

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Cell adhesion molecules play a central role in neural development and are also critically involved in axonal regeneration and synaptic plasticity in the adult nervous system. We investigated whether the neural cell adhesion molecule L1 was capable of stimulating survival and differentiation in the mid-brain dopaminergic neurons which degenerate in Parkinson's disease. Monoclonal L1 antibodies, known to enhance neurite outgrowth, were substrate-coated or added at the time of plating to medium of cultures containing mid-brain dopaminergic neurons from 14-day-old fetal rats. Tritiated dopamine uptake per well and the number of tyrosine hydroxylase-immunopositive neurons increased in a dose-dependent manner with increasing concentrations of L1 antibody, suggesting that L1 acts directly or indirectly as a growth factor for dopaminergic neurons. A monoclonal L1 antibody not enhancing neurite outgrowth was ineffective. The growth-promoting effects of L1 antibodies on dopaminergic neurons in culture did not appear to be mediated by the cAMP-activated protein kinase A pathway, since combined treatment with a phosphodiesterase inhibitor had only additive effects on the L1-induced increase of dopamine uptake, and in addition, antibodies against L1 failed to protect cultures of dopaminergic neurons against the neurotoxin MPP+, whereas pretreatment with forskolin and phosphodiesterase type-IV inhibitors was strongly protective.

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“…Glial cells, which lie in close association with the neurons in the brain, could serve as a buffer against toxic substances. Glial cells also secrete growth factors and other trophic substances that can protect neurons from damage (Park and Mytilineou, 1992;O'Malley et al, 1994;Sullivan et al, 1998). Indeed, glial-secreted factors have been shown to protect from levodopa toxicity in vitro (Mena et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Levodopa Is Toxic to Dopamine Neurons in an in Vitro but Not an in Vivo Model of Oxidative Stress

Mytilineou

Walker²,

JnoBaptiste³

et al. 2003

J Pharmacol Exp Ther

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Levodopa is the "gold standard" for the symptomatic treatment of Parkinson's disease (PD). There is a theoretical concern, however, that levodopa might accelerate the rate of nigral degeneration, because it undergoes oxidative metabolism and is toxic to cultured dopaminergic neurons. Most in vivo studies do not show evidence of levodopa toxicity; levodopa is not toxic to normal rodents, nonhuman primates, or humans and is not toxic to dopamine neurons in dopamine-lesioned rodents or nonhuman primates in most studies. However, the potential for levodopa to be toxic in vivo has not been tested under conditions of oxidative stress such as exist in PD. To assess whether levodopa is toxic under these circumstances, we have examined the effects of levodopa on dopamine neurons in mesencephalic cultures and rat pups in which glutathione synthesis has been inhibited by L-buthionine sulfoximine. Levodopa toxicity to cultured dopaminergic neurons was enhanced by glutathione depletion and diminished by antioxidants. In contrast, treatment of neonatal rats with levodopa, administered either alone or in combination with glutathione depletion, did not cause damage to the dopamine neurons of the substantia nigra or changes in striatal levels of dopamine and its metabolites. This study provides further evidence to support the notion that although levodopa can be toxic to dopamine neurons in vitro, it is not likely to be toxic to dopamine neurons in vivo and specifically in conditions such as PD.

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Protection from 1-methyl-4-phenylpyridinium (MPP+) toxicity and stimulation of regrowth of MPP+-damaged dopaminergic fibers by treatment of mesencephalic cultures with EGF and basic FGF

Cited by 91 publications

References 66 publications

Rescue of Mesencephalic Dopamine Neurons by Anticancer Drug Cytosine Arabinoside

Rescue of Mesencephalic Dopamine Neurons by Anticancer Drug Cytosine Arabinoside

L1 neural cell adhesion molecule is a survival factor for fetal dopaminergic neurons

Levodopa Is Toxic to Dopamine Neurons in an in Vitro but Not an in Vivo Model of Oxidative Stress

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