Abstract
BackgroundWe previously demonstrated that subcutaneous administration of PT320, a sustained-release (SR) form of exendin-4, resulted in the long-term maintenance of steady-state exenatide (exendin-4) plasma and target levels in 6-hydroxydopamine (6-OHDA)-pretreated animals. Additionally, pre- or post-treatment with PT320 mitigated the early stage of 6-OHDA-induced dopaminergic neurodegeneration. The purpose of this study was to evaluate the effect of PT320 on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the rat 6-OHDA model of Parkinson’s disease.MethodsAdult male Sprague–Dawley rats were unilaterally lesioned in the right medial forebrain bundle by 6-OHDA. L-DOPA and benserazide were given daily for 22 days, starting from 4 weeks after lesioning. PT320 was co-administered weekly for 3 weeks. AIM was evaluated on days 1, 16, and 22 after initiating L-DOPA/benserazide + PT320 treatment. Brain tissues were subsequently collected for HPLC measurements of dopamine (DA) and metabolite concentrations.ResultsL-DOPA/benserazide increased AIMs of limbs and axial as well as the sum of all dyskinesia scores (ALO) over 3 weeks. PT320 significantly reduced the AIM scores of limbs, orolingual, and ALO. Although PT320 did not alter DA levels in the lesioned striatum, PT320 significantly attenuated 6-OHDA-enhanced DA turnover.ConclusionPT320 attenuates L-DOPA/benserazide-induced dyskinesia in a 6-OHDA rat model of PD and warrants clinical evaluation to mitigate Parkinson’s disease in humans.
Highlights
Levodopa, known as L-3,4-dihydroxyphenylalanine (LDOPA), is the precursor of dopamine (DA) and is currently the most commonly used medication for Parkinson’s disease (PD)
We previously demonstrated that subcutaneous administration of PT320, a sustained-release (SR) form of exendin-4, resulted in the long-term maintenance of steady-state exenatide plasma and target levels in 6-hydroxydopamine (6OHDA)-pretreated animals
In the animals receiving PT320, the abnormal involuntary movements (AIMs) score was not significantly correlated with the duration of L-DOPA/benserazide treatment (Figure 3A1, all dyskinesia scores (ALO), p = 0.081; B1: limb, p = 0.068; C: axial, p = 0.051). These data suggest that L-DOPA/benserazide treatment time-dependently increased dyskinesia, which was attenuated by PT320
Summary
Known as L-3,4-dihydroxyphenylalanine (LDOPA), is the precursor of dopamine (DA) and is currently the most commonly used medication for Parkinson’s disease (PD). Chronic administration of L-DOPA is often associated with abnormal involuntary movements (AIMs), called levodopa-induced dyskinesia (LID) in PD patients. Clinical studies have shown that 20–50% of PD patients developed dyskinesia within 5 years after the initiation of L-DOPA treatment (Rascol et al, 2000; Manson et al, 2012; Bjornestad et al, 2016). Other studies suggest that the disease severity and dose of L-DOPA are more important than the duration of L-DOPA treatment for the development of LID (Nutt et al, 2010; Espay et al, 2018). The purpose of this study was to evaluate the effect of PT320 on L-3,4-dihydroxyphenylalanine (LDOPA)-induced abnormal involuntary movements (AIMs) in the rat 6-OHDA model of Parkinson’s disease
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