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

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.