Levodopa/benserazide microspheres reduced levodopa-induced dyskinesia by downregulating phosphorylated GluR1 expression in 6-OHDA-lesioned rats

Drug Des Devel Ther. 2012;6:341-7. doi: 10.2147/DDDT.S38008. Epub 2012 Nov 20.

Abstract

Background: Levodopa is the gold standard in the treatment of Parkinson's disease (PD). However, long-term levodopa replacement therapy is accompanied by abnormal involuntary movements (AIMs), known as levodopa-induced dyskinesia (LID). Until now, the precise mechanisms of LID were only partially understood. Previous studies have shown that continuous dopamine stimulation was helpful in reducing the expression of LID. In addition to dopamine D1 receptor, glutamatergic receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor also contribute to the expression of LID. The current authors have previously reported that levodopa/benserazide-loaded microspheres could ameliorate the expression of LID by reducing the protein kinase A signaling pathway in dyskinetic rats. However, whether AMPA receptor is involved in the mechanism by which levodopa/benserazide-loaded microspheres ameliorate the expression of LID in dyskinetic rats was unknown.

Methods: In the present study, as reported previously, levodopa and benserazide were loaded by poly(lactic-co-glycolic acid) microspheres, which can release levodopa and benserazide in a sustained manner. 6-Hydroxydopamine was injected into the right medial forebrain bundle to produce a rat model of PD. Then valid PD rats were treated with levodopa plus benserazide for 3 weeks to induce a rat model of LID. Dyskinetic rats were treated with levodopa/beserazide-loaded microspheres containing levodopa (6 mg/kg) plus benserazide (15 mg/kg) or same dose of levodopa plus benserazide. Abnormal involuntary movements were measured in rats on days 1, 5, 10, 15, and 20 during the treatment. The levels of GluR1 at serine-831 (pGluR1S831) and serine-845 (pGluR1S845) were determined by Western blot. Arc and proenkephalin (Penk) levels were measured by real-time polymerase chain reaction.

Results: Three-week levodopa plus benserazide treatment induced dyskinesia in PD rats. Levodopa/benserazide-loaded microsphere-treated dyskinetic rats showed lower AIM scores than levodopa plus benserazide-treated dyskinetic rats. Microsphere treatment downregulated the phosphrylated levels of pGluR1S831 and pGluR1S845 in the striatum of dyskinetic rats. In addition, microsphere treatment reduced the levels of Arc and Penk.

Conclusion: These data indicated that levodopa/benserazide-loaded microspheres could be used to ameliorate the expression of LID by reducing the expression of pGluR1S831 and pGluR1S845 as well as Arc and Penk.

Keywords: Arc; levodopa/beserazide-loaded microspheres; proenkephalin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / administration & dosage
  • Antiparkinson Agents / pharmacology
  • Antiparkinson Agents / toxicity*
  • Benserazide / administration & dosage
  • Benserazide / pharmacology
  • Benserazide / toxicity*
  • Blotting, Western
  • Delayed-Action Preparations
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Drug Carriers / chemistry
  • Drug Combinations
  • Dyskinesia, Drug-Induced / etiology*
  • Dyskinesia, Drug-Induced / prevention & control
  • Female
  • Lactic Acid / chemistry
  • Levodopa / administration & dosage
  • Levodopa / pharmacology
  • Levodopa / toxicity*
  • Microspheres
  • Oxidopamine / toxicity
  • Parkinsonian Disorders / drug therapy
  • Phosphorylation / drug effects
  • Polyglycolic Acid / chemistry
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Receptors, AMPA / genetics*

Substances

  • Antiparkinson Agents
  • Delayed-Action Preparations
  • Drug Carriers
  • Drug Combinations
  • Receptors, AMPA
  • benserazide, levodopa drug combination
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Levodopa
  • Benserazide
  • Oxidopamine
  • glutamate receptor ionotropic, AMPA 1