Effects of orally administered levodopa on mesencephalic dopaminergic neurons undergoing a degenerative process

Ferrario, Juan E.; Delfino, Marina; Stefano, Andrea V.; Zbarsky, Virginia; Douhou, Aicha; Murer, Mario Gustavo; Raisman‐Vozari, Rita; Gershanik, Oscar S.

doi:10.1016/j.neures.2003.08.001

Cited by 17 publications

(10 citation statements)

References 26 publications

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“…The earlier time point examined here, however, may be more reminiscent of the clinical situation of PD. Ferrario et al [22] attempted to address the effects of L-DOPA during active degeneration but did not see any effects. However, in that study L-DOPA exposure began only 1 day after exposure to 6-OHDA, which was delivered to the striatum rather than the MFB, so it is not comparable to this work.…”

Section: Discussionmentioning

confidence: 99%

Striatal Dopaminergic Fiber Recovery After Acute l-DOPA Treatment in 6-Hydroxydopamine (6-OHDA) Lesioned Rats

Fang

Yin

et al. 2010

Cell Biochem Biophys

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In order to examine the acute effects of L: -DOPA treatment following 6-hydroxydopamine (6-OHDA) injection into rat medial forebrain bundle (MFB). Sprague-Dawley rats (n = 48) received either 6-OHDA, via intracranial unilateral injection, into the MFB (experimental group) or saline 0.9% (control group). Administration of L: -DOPA or saline 0.9% began 1 month after the 6-OHDA injection for 10 consecutive days. Within 3 days, an increase in the density of striatal tyrosine hydroxylase (TH) immunoreactive fibers within the striatum, when compared to the control group was observed. There was no difference in the loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons between. The greater density of TH fibers in the striatum following L: -DOPA may be related to recovery of the DA phenotype and/or sprouting of TH axon terminals. Only animals with severe cell loss in the SNpc experienced abnormal involuntary movements (AIMs) or "dyskinesias" in response to L: -DOPA, which did not correlate with striatal TH fiber density, suggesting that induction of TH-positive fibers does not contribute to the occurrence of dyskinesia. The relationship between cell loss, fiber density and AIM to the abundance of markers of microglial activation were also examined. Iba-1, a microglial marker, immunoreactivity was not affected by L: -DOPA treatment, was not correlated with the severity of AIM indicating that microglial activation does not contribute to dyskinetic phenomena.

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Section: Discussionmentioning

confidence: 99%

Striatal Dopaminergic Fiber Recovery After Acute l-DOPA Treatment in 6-Hydroxydopamine (6-OHDA) Lesioned Rats

Fang

Yin

et al. 2010

Cell Biochem Biophys

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“…The toxicity of levodopa and DA has been well documented in many experiments [3][4][5] ; we and others first demonstrated that levodopa itself can become a levodopa quinone radical and that the repeated administration of levodopa increases lipid peroxidation in the striatum of parkinsonian mice, [6][7][8][9] although there is a controversy regarding the demonstration of nontoxic or somewhat protective effects of levodopa in a naive animal or a moderately lesioned parkinsonian model. [10][11][12][13] DA is stable in the synaptic vesicle under normal conditions. However, an excess amount of cytosolic DA outside the vesicle in the damaged DA neurons is thought to exert neurotoxicity through the generation of reactive oxygen species (ROS) and reactive DA quinones as dopaminergic neuron-specific oxidative stress when levodopa is administered to the damaged dopaminergic neuronal system of Parkinson disease.…”

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confidence: 98%

Dopamine Agonist Pergolide Prevents Levodopa-Induced Quinoprotein Formation in Parkinsonian Striatum and Shows Quenching Effects on Dopamine-Semiquinone Generated in Vitro

Miyazaki

Asanuma²,

Díaz-Corrales

et al. 2005

Clinical Neuropharmacology

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The neurotoxicity of dopamine (DA) quinones that appears in dopaminergic neuron-specific oxidative stress has recently been shown to play a role in the pathogenesis and/or progression of Parkinson disease. To clarify the effects of a DA agonist, pergolide, on the levodopa-induced elevation of quinones, the authors examined striatal changes in quinoprotein using a hemi-parkinsonian mouse model. The level of striatal quinoprotein was significantly elevated specifically on the parkinsonian side, but not on the control side, after repeated levodopa administration. This levodopa-induced increase in striatal quinoprotein was almost completely suppressed by adjunctive administration with pergolide on the lesioned side. Furthermore, it was clarified that pergolide scavenged DA-semiquinones generated in vitro in a dose-dependent manner. These suppressive and quenching effects of pergolide against cytotoxic DA quinones may play a key role in its neuroprotective mechanism in the parkinsonian brain.

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“…The nigrostriatal dopaminergic neurons were lesioned unilaterally by injections of 6‐OHDA in the right striatum, as previously described (Ferrario et al. 2003; Debeir et al.…”

Section: Methodsmentioning

confidence: 99%

Pleiotrophin receptor RPTP‐ζ/β expression is up‐regulated by l‐DOPA in striatal medium spiny neurons of parkinsonian rats

Ferrario

Rojas-Mayorquín

Saldaña-Ortega

et al. 2008

Journal of Neurochemistry

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l‐DOPA is still the drug of choice to treat Parkinson’s disease although adverse side effects appear after several years of treatment. These are thought to be the consequence of plastic re‐arrangements of the nigrostriatal connections, such as sprouting of the dopaminergic terminals or post‐synaptic changes. Pleiotrophin, a trophic factor that we have shown to be up‐regulated in the striatum of parkinsonian rats after long‐term l‐DOPA treatment may play a role in these plastic changes. To determine whether one of the three known pleiotrophin receptors [N‐syndecan, receptor protein tyrosine phosphatase type zeta beta (RPTP‐ζ/β) and anaplastic lymphoma kinase] might be implicated in these putative plastic effects, we quantified their expression levels by real‐time RT‐PCR in the striatum and mesencephalon of rats with partial lesions of the nigrostriatal pathway undergoing l‐DOPA treatment. Both pleiotrophin and RPTP‐ζ/β expression was up‐regulated in the striatum but not in the mesencephalon of lesioned rats and RPTP‐ζ/β expression was even further increased by l‐DOPA. The levels of the RPTP‐ζ/β protein were also increased in the striatum of l‐DOPA‐treated lesioned rats. Immunofluorescence labeling showed the protein to be constitutively expressed in striatal medium spiny neurons, which are innervated by both the corticostriatal glutamatergic and nigrostriatal dopaminergic systems. RPTP‐ζ/β might therefore be implicated in the plastic changes triggered by l‐DOPA treatment and might merit further study as a potential candidate for Parkinon’s disease therapy.

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Effects of orally administered levodopa on mesencephalic dopaminergic neurons undergoing a degenerative process

Cited by 17 publications

References 26 publications

Striatal Dopaminergic Fiber Recovery After Acute l-DOPA Treatment in 6-Hydroxydopamine (6-OHDA) Lesioned Rats

Striatal Dopaminergic Fiber Recovery After Acute l-DOPA Treatment in 6-Hydroxydopamine (6-OHDA) Lesioned Rats

Dopamine Agonist Pergolide Prevents Levodopa-Induced Quinoprotein Formation in Parkinsonian Striatum and Shows Quenching Effects on Dopamine-Semiquinone Generated in Vitro

Pleiotrophin receptor RPTP‐ζ/β expression is up‐regulated by l‐DOPA in striatal medium spiny neurons of parkinsonian rats

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