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

Abstract

BackgroundLevodopa 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.MethodsIn 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.ResultsThree-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.ConclusionThese 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.

Ranitidine reduced levodopa-induced dyskinesia in a rat model of Parkinson’s disease

“…Striatal dynorphin levels are then increased in PD rats after activation of these two genes 36. As we know, dynorphin is closely correlated with expression of LID 7. In the present study, long-term treatment with levodopa induced an increase in Arc and Penk levels.…”

“…Arc and Penk levels were measured by real-time PCR, as previously reported 7. The rats were sacrificed by deep anesthesia after their last behavioral test, after which striatal tissues from the sham and 6-OHDA-lesioned rats treated with vehicle or pulsatile levodopa alone or in combination with ranitidine were homogenized, and total RNA was extracted using Trizol reagent (Life Technologies, Carlsbad, CA, USA).…”

Potential Effects of Pomegranate Juice in Attenuating LID in Mice Model of Parkinson Disease

“…3 There have been efforts to reduce LID via thalamotomy and some adjunct medications. The "oxidative stress" hypothesis suggests that the nigrostriatal cell death observed in PD is due to the MPTP-mediated formation of hydroxyl and superoxide radicals that may play a causal role in PD.…”

Prospects for polymer therapeutics in Parkinson's disease and other neurodegenerative disorders

“…Two further studies showed that the delivery of levodopa methyl ester in conjunction with benserazide (a peripheral dopa-decarboxylase inhibitor) via PLGA particles could reduce l-DOPA induced dyskinesias [183,185]. A reduction in phosphorylation of the non-dopaminergic glutamatergic receptor ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) was observed [185], a receptor previously shown to be involved in l-DOPA induced dyskinesias [186].…”

“…A reduction in phosphorylation of the non-dopaminergic glutamatergic receptor ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) was observed [185], a receptor previously shown to be involved in l-DOPA induced dyskinesias [186].…”