Sustained-release formulation of levodopa methyl ester/benserazide for prolonged suppressing dyskinesia expression in 6-OHDA-leisoned rats

Ren, Tiantian; Yang, Xinxin; Wu, Na; Cai, Yunpeng; Liu, Zhenguo; Yuan, Weien

doi:10.1016/j.neulet.2011.07.042

Cited by 29 publications

(20 citation statements)

References 26 publications

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“…Ren et al, [19] encapsulated L-DOPA methyl ester, a highly soluble prodrug hydrolysable by plasma esterases, together with benserazide, a peripheral decarboxylase inhibitor in PLGA MP (LP-be-MP). MP subcutaneously administered improved motor function and stepping of the lesioned forepaw in the 6-hydroxydopamine (6-OHDA) PD rat model.…”

Section: Dds For Levodopa Deliverymentioning

confidence: 99%

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

2013

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Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease.Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood brain barrier and target a specific region are still needed.Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly-targeted drugs. The advent of new molecular and cellular targets like α-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients.

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Section: Dds For Levodopa Deliverymentioning

confidence: 99%

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

2013

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“…7 Benserazide-loaded nanoparticles were prepared according to the water-in-oil-in-water emulsion solvent evaporation method. Benserazide was directly added to the DCM solution of poly(lactic-co-glycolic acid) 50/50 3A (47 kDa, 5% wt/wt) and polylactic acid (83 kDa, 7.5% wt/wt).…”

Section: Preparation Of Ldme/benserazide-loaded Nanoparticlesmentioning

confidence: 99%

“…The rest of the procedure was the same as the method previously reported. 7 If the salt or the organic phase was not removed completely, nanoparticles would gather together and the material would be difficult to inject. When the nanoparticles were initially formed by fast stirring, care had to be taken not to let the nanoparticles be exposed to the air.…”

Section: Preparation Of Ldme/benserazide-loaded Nanoparticlesmentioning

confidence: 99%

“…We recently reported that levodopa methyl ester (LDME)/benserazide-loaded nanoparticles can be used to treat PD motor symptoms and reduce the expression of LID in a rat model of PD. 7 However, whether LDME/ benserazide-loaded nanoparticles can be used to ameliorate established levodopa-induced dyskinesia in rats is not well understood. In this study, dyskinesia was induced in rats by repeated administration of levodopa.…”

Section: Introductionmentioning

confidence: 99%

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Controlled-release levodopa methyl ester/benserazide-loaded nanoparticles ameliorate levodopa-induced dyskinesia in rats

Yang¹,

Zheng²,

Cai³

et al. 2012

IJN

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Background: Levodopa remains the most effective drug in the treatment of Parkinson's disease. However, long-term administration of levodopa induces motor complications, such as levodopa-induced dyskinesia. The mechanisms underlying levodopa-induced dyskinesia are not fully understood. Methods: In this study, we prepared levodopa methyl ester (LDME)/benserazide-loaded nanoparticles, which can release LDME and benserazide in a sustained manner. Dyskinesia was induced in rats by repeated administration of levodopa then treated with LDME plus benserazide or the same dose of LDME/benserazide-loaded nanoparticles. Apomorphine-induced rotations and abnormal involuntary movements (AIMs) were measured on treatment days 1, 5, 10, 15, and 20. In addition, the levels of phosphorylated dopamine-and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa, extracellular signal-regulated kinases 1/2, and ∆fosB were determined by Western blot. Tau levels were determined by Western blot and immunohistochemistry. Dynorphin levels in the striatum and cortex of rats were measured using enzyme-linked immunosorbent assay. Results: Over the course of levodopa treatment, the rats developed abnormal AIMs, classified as locomotive, axial, orolingual, and forelimb dyskinesia. The degree of reduction of apomorphine-induced rotations was comparable in dyskinetic rats treated with LDME plus benserazide or LDME/benserazide-loaded nanoparticles. The axial, limb, and orolingual (ALO) AIMs of dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 14 ± 2.5, 9 ± 2.0, and 10 ± 2.1 on treatment days 10, 15, and 20, respectively, which were significantly reduced compared with dyskinetic rats treated with LDME plus benserazide (25 ± 3.7, 27 ± 3.8, and 25 ± 3.5, respectively). The locomotive AIMs of dyskinetic rats treated with LDME/ benserazide-loaded nanoparticles were 2.3 ± 0.42, 1.7 ± 0.35, and 1.6 ± 0.37 on treatment days 10, 15, and 20, respectively, which were also reduced compared with dyskinetic rats treated with LDME plus benserazide (4.4 ± 0.85, 4.7 ± 0.95 and 4.8 ± 0.37, respectively). Western blot showed that the levels of phosphorylated dopamine-and cyclic adenosine monophosphateregulated phosphoprotein of 32 kDa, extracellular signal-regulated kinases 1/2, tau, and ∆fosB in dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 134.6 ± 14.1, 174.9 ± 15.1, 134.2 ± 19.3, and 320.5 ± 32.8, respectively, which were significantly reduced compared with those of dyskinetic rats treated with LDME plus benserazide (210.3 ± 19.7, 320.8 ± 21.9, 340.4 ± 27.1, and 620.7 ± 48.3, respectively). Immunohistochemistry indicated that the level of phosphorylated tau was (7.2 ± 1.1) × 10 4 in dyskinetic rats treated with LDME/ benserazide-loaded nanoparticles. However, the tau level was only (14.6 ± 2.3) × 10 4 in LDME plus benserazide-treated dyskinetic rats. There was a significant difference between the two groups. Enzyme-linked immunosorbent assay showed that dynorphin levels in the striatum and cortex of dyski...

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“…When administered in the form of microspheres into 6-OHDA-lesioned rat model, levodopa methyl ester/ benserazide achieves sustained release and markedly attenuates apomorphine-induced rotations and rectifies the imbalance steps of the parkinsonian rats [124].…”

Section: Sustained-release Formulation Of Levodopa Methyl Ester/bensementioning

confidence: 99%

Animal Models of Parkinson's Disease: A Gateway to Therapeutics?

Sayana

Jankovic

2014

Neurotherapeutics

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Parkinson's disease (PD) is a progressive, neurodegenerative disorder of unknown etiology, although a complex interaction between environmental and genetic factors has been implicated as a pathogenic mechanism of selected neuronal loss. A better understanding of the etiology, pathogenesis, and molecular mechanisms underlying the disease process may be gained from research on animal models. While cell and tissue models are helpful in unraveling involved molecular pathways, animal models are much better suited to study the pathogenesis and potential treatment strategies. The animal models most relevant to PD include those generated by neurotoxic chemicals that selectively disrupt the catecholaminergic system such as 6-hydroxydopamine; 1-methyl-1,2,3,6-tetrahydropiridine; agricultural pesticide toxins, such as rotenone and paraquat; the ubiquitin proteasome system inhibitors; inflammatory modulators; and several genetically manipulated models, such as α-synuclein, DJ-1, PINK1, Parkin, and leucine-rich repeat kinase 2 transgenic or knock-out animals. Genetic and nongenetic animal models have their own unique advantages and limitations, which must be considered when they are employed in the study of pathogenesis or treatment approaches. This review provides a summary and a critical review of our current knowledge about various in vivo models of PD used to test novel therapeutic strategies.

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Sustained-release formulation of levodopa methyl ester/benserazide for prolonged suppressing dyskinesia expression in 6-OHDA-leisoned rats

Cited by 29 publications

References 26 publications

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

Controlled-release levodopa methyl ester/benserazide-loaded nanoparticles ameliorate levodopa-induced dyskinesia in rats

Animal Models of Parkinson's Disease: A Gateway to Therapeutics?

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