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

Abstract

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 ΔfosB 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 monophosphate-regulated phosphoprotein of 32 kDa, extracellular signal-regulated kinases 1/2, tau, and ΔfosB 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 dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 5.7 ± 1.2 and 4.8 ± 0.87, respectively, which were significantly reduced compared with LDME plus benserazide-treated dyskinetic rats (13.3 ± 2.1 and 8.1 ± 1.1 for the striatum and cortex, respectively).

CONCLUSION:

Results suggest that LDME/benserazide-loaded nanoparticles can be used to reduce the expression of dyskinesia in dyskinetic rats.

• Authors: Xinxin Yang, Ruiyuan Zheng, Yunpeng Cai, Meiling Liao, Weien Yuan, Zhenguo Liu
• Journal: International journal of nanomedicine (Int J Nanomedicine) Vol. 7 Pg. 2077-86 ( 2012) ISSN: 1178-2013 [Electronic] New Zealand
• PMID: 22619544 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• Dopamine and cAMP-Regulated Phosphoprotein 32
• Drug Carriers
• Fosb protein, rat
• Mapt protein, rat
• Ppp1r1b protein, rat
• Proto-Oncogene Proteins c-fos
• tau Proteins
• Levodopa
• Dynorphins
• Benserazide
• Mitogen-Activated Protein Kinase Kinases
• levodopa methyl ester

Topics

• Animals
• Antiparkinson Agents (administration & dosage, adverse effects)
• Benserazide (administration & dosage)
• Brain (drug effects, metabolism)
• Dopamine and cAMP-Regulated Phosphoprotein 32 (metabolism)
• Drug Carriers (chemistry)
• Drug Delivery Systems
• Dynorphins (metabolism)
• Dyskinesia, Drug-Induced (drug therapy, physiopathology)
• Levodopa (administration & dosage, adverse effects, analogs & derivatives)
• Male
• Microscopy, Electron, Scanning
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Nanomedicine
• Nanoparticles (chemistry, ultrastructure)
• Particle Size
• Phosphorylation
• Proto-Oncogene Proteins c-fos (metabolism)
• Rats
• tau Proteins (metabolism)