Modification of Parkinsonism — Chronic Treatment with L-Dopa

Cotzias, George C.; Papavasiliou, Paul S.; Gellene, Rosemary A.

doi:10.1056/nejm196902132800701

Cited by 1,179 publications

(319 citation statements)

References 14 publications

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“…For the past five decades, levodopa has been the gold-standard therapy for the motor symptoms of the disease. However, the introduction of levodopa also led to new and significant challenges in the clinical management of patients with PD, specifically the development of long-term motor complications, such as involuntary movements (dyskinesias; Cotzias et al, 1969;Godwin-Austen, 1973;Simuni and Hurtig, 2008) (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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Section: Introductionmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

View full text Add to dashboard Cite

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“…12 L-DOPA is α-carboxy dopamine, which, in the presence of dopamine decarboxylase, gets converted into dopamine in the surviving dopamine neurons. 12,13 This therapy works well in the early stages of the disease process by restoring motor function in virtually all patients. However, long-term use of L-DOPA gives rise to motor fluctuations with dyskinesias as well as a decrease in the duration of the response to a given L-DOPA dose.…”

Section: ■ Introductionmentioning

confidence: 99%

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

Santra

Shah

et al. 2013

ACS Chem. Neurosci.

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In this Article, we have demonstrated the in vivo efficacy of D-512 and D-440 in a 6-OHDA-induced unilaterally lesioned rat model experiment, a Parkinson's disease animal model. D-512 is a novel highly potent D2/D3 agonist, and D-440 is a novel highly selective D3 agonist. We evaluated the neuroprotective properties of D-512 and D-440 in the dopaminergic MN9D cells. Cotreatment of these two drugs with 6-OHDA and MPP+ significantly attenuated and reversed 6-OHDA-and MPP+-induced toxicity in a dosedependent manner in the dopaminergic MN9D cells. The inhibition of caspase 3/7 and lipid peroxidation activities along with the restoration of tyrosine hydroxylase levels by D-512 in 6-OHDA-treated cells may partially explain the mechanism of its neuroprotective property. Furthermore, studies were carried out to elucidate the time-dependent changes in the pERK1/2 and pAkt, two kinases implicated in cell survival and apoptosis, levels upon treatment with 6-OHDA in presence of D-512. The neuroprotective property exhibited by these drugs was independent of their dopamine-agonist activity, which is consistent with our multifunctional drug-development approach that is focused on the generation of disease-modifying symptomatic-treatment agents for Parkinson's disease.

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“…Levo-dopa (L-dopa), the direct precursor of dopamine, remains the primary treatment choice since first use over 30 years ago (Markham & Diamond, 1981;Silva et al, 1997). L-Dopa can relieve the major clinical symptom of PD, i.e., the inability to initiate voluntary movements (Cotzias et al, 1969). However, the success of long-term L-dopa therapy in PD is compromised by the almost invariable intrusion of dyskinesias during the periods of the day when medication is most effective (Cotzias et al, 1969;Ruberg et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…L-Dopa can relieve the major clinical symptom of PD, i.e., the inability to initiate voluntary movements (Cotzias et al, 1969). However, the success of long-term L-dopa therapy in PD is compromised by the almost invariable intrusion of dyskinesias during the periods of the day when medication is most effective (Cotzias et al, 1969;Ruberg et al, 1995). Even after treatment with L-dopa, with or without other dopaminergic drugs for more than 5 or 6 years, a majority of patients develop response fluctuations, dyskinesia or dystonia (Papapetropoulos et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Neurobehavioral assessment of hydroalcoholic extract ofTrigonella foenum-graecumseeds in rodent models of Parkinson’s disease

Gaur

Bodhankar

Thakurdesai

2013

Pharmaceutical Biology

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Context: Neuroprotective therapy to rescue dopaminergic neurons is an important trait in the management of Parkinson's disease (PD).Objective: The present study identified and evaluated SFSE-T, a standardized hydroalcoholic extract of Trigonella foenum-graecum L. seeds (Fabaceae), in animal models of PD. Materials and methods: The identification of SFSE-T was carried out by high-performance liquid chromatography for the marker compound trigonelline (TGN). The effects of single dose oral treatment of SFSE-T (10, 30 or 100 mg/kg) were studied using animal models of PD, namely, 6-hydroxydopamine (6-OHDA)-induced unilateral lesions in rats, and 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration in C57BL/6 mice. The effects of SFSE-T on monoamino oxidase (MAO) enzyme in vitro as well as possible side effects of SFSE-T in vivo were also evaluated. Results: The concentration of TGN in a test sample of SFSE-T was found to be 82%. SFSE-T (30 mg/kg, oral) showed a significant increase in the number of ipsilateral rotations (45.67 rotations in 30-min period) as compared with vehicle control group (no rotations) when tested in 6-OHDA-induced unilateral lesioned rats. SFSE-T (30 mg/kg, oral) showed significant reversal of motor dysfunction (spontaneous motor activity scores, speed, distance traveled and number of square crossed) caused by MPTP induced lesions in C57BL/6 mice in pretreatment (1 h) schedule but not in post-treatment (1 h) schedule. SFSE-T neither showed anticholinergic effects nor showed selective MAO-B enzyme inhibition in vitro. Discussion and conclusion: SFSE-T showed reversal of motor symptoms in an animal model of PD probably through neuroprotective properties. KeywordsAnimal model of disease, fenugreek, 6-hydroxydopamine lesions, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced neurotoxicity, neurodegenerative disease History

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Modification of Parkinsonism — Chronic Treatment with L-Dopa

Cited by 1,179 publications

References 14 publications

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

Neurobehavioral assessment of hydroalcoholic extract ofTrigonella foenum-graecumseeds in rodent models of Parkinson’s disease

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