Long‐term administration of L‐DOPA does not damage dopaminergic neurons in the mouse

Hefti, Franz; Melamed, Eldad; Bhawan, Jag; Wurtman, Richard J.

doi:10.1212/wnl.31.9.1194

Cited by 116 publications

(49 citation statements)

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“…Although L-DOPA toxicity has been reported previously in catecholaminergic cells in vitro (11)(12)(13)(14)(15), several studies have examined the effect of chronic administration of L-DOPA in vivo in normal healthy animals and found no evidence of neuronal damage, although extensive quantitation of the number of nigral cells remaining after drug treatment was not performed (16,17). Damage to nigrostriatal dopaminergic neurons could not be detected after chronic treatment of rats (16) that after a toxic insult, necrotic cell death will occur irrespective of other factors, whereas because apoptosis is an active cellular process, the susceptibility of a cell to undergo apoptotic cell death in response to a certain stimuli can (38).…”

Section: Resultsmentioning

confidence: 99%

“…However, this hypothesis has remained unsubstantiated due to a lack of evidence supporting L-DOPA toxicity in vivo. It has been shown in both rats ( 16) and mice ( 17) that long-term administration of L-DOPA does not cause detectable damage to nigrostriatal dopaminergic neurons. Furthermore, no evidence of damage to nigral neurons was found in a normal individual consuming large amounts of L-DOPA over a prolonged period ( 18).…”

Section: Introductionmentioning

confidence: 99%

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Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson's disease.

Walkinshaw¹,

Waters²

1995

J. Clin. Invest.

232

117

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The hypothesis that L-DOPA therapy in Parkinson's disease may augment neuronal damage and thus accelerate the progression of the disease remains controversial. In this study, we demonstrate that L-DOPA induces death of catecholaminergic cells in vitro via an active program of apoptosis. Treatment of PC12 cells with clinically applicable concentrations of L-DOPA (25-100 ,uM) induced cell death via a mechanism which exhibited morphological and biochemical characteristics of apoptosis, including chromatin condensation, membrane blebbing, and internucleosomal DNA fragmentation. L-DOPA-induced apoptosis was cell and drugtype specific. Toxicity is an intrinsic property of the drug molecule since it was not suppressed by inhibiting conversion of L-DOPA to dopamine. However, L-DOPA toxicity was inhibited by antioxidants, suggesting that activation of apoptosis is mediated by oxygen radicals. Our finding that L-DOPA-induced cell death in vitro occurs via apoptosis explains the lack of evidence supporting its toxicity in vivo, since apoptotic neurons are rapidly phagocytosed in vivo without causing damage to surrounding tissue. Furthermore, since apoptosis is an active cellular program which can be modulated, we suggest clinical approaches for decreasing L-DOPA toxicity, thus preventing acceleration of neuronal damage in Parkinson's disease. (J. Clin. Invest. 1995Invest. . 95:2458Invest. -2464

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson's disease.

Walkinshaw¹,

Waters²

1995

J. Clin. Invest.

232

117

View full text Add to dashboard Cite

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“…Toxicity is seen with concentrations that are substantially higher than used in the treatment of patients with PD and low concentrations are actually protective, possibly because they induce upregulation of Bcl-2 and glutathione. 236 Levodopa has not been shown to be toxic to dopamine neurons in normal animals or humans, 237,238 and does not increase neuronal degeneration in dopamine-lesioned animals. 239 It is possible that the situation may be different in PD, in which there is oxidative stress and compromised defense mechanisms in the SNc.…”

Section: Apoptosismentioning

confidence: 99%

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Olanow¹,

Stern²,

Sethi³

2009

Neurology

773

658

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Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches. 1 PD is the second most common neurodegenerative disorder, with an average age at onset of about 60 years. An estimated 5 million people throughout the world have PD, with 1 million individuals each in the United States and in Europe with the disorder. PD affects approximately 0.3% of the population and 1% to 2% of those older than 60 years.2 With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase dramatically in the coming decades.

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“…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.…”

mentioning

confidence: 99%

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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Long‐term administration of L‐DOPA does not damage dopaminergic neurons in the mouse

Cited by 116 publications

References 0 publications

Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson's disease.

Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson's disease.

The scientific and clinical basis for the treatment of Parkinson disease (2009)

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

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