Abstract
BackgroundAlthough the dopamine precursor L-3, 4-dihydroxyphenylalanine (l-dopa) remains the gold standard pharmacological therapy for patients with Parkinson’s disease (PD), long-term treatment with this drug has been known to result in several adverse effects, including l-dopa-induced dyskinesia (LID). Recently, our group reported that KD5040, a modified herbal remedy, had neuroprotective effects in both in vitro and in vivo models of PD. Thus, the present study investigated whether KD5040 would have synergistic effects with l-dopa and antidyskinetic effects caused by l-dopa as well.MethodsThe effects of KD5040 and l-dopa on motor function, expression levels of substance P (SP) and enkephalin (ENK) in the basal ganglia, and glutamate content in the motor cortex were assessed using behavioral assays, immunohistochemistry, Western blot analyses, and liquid chromatography tandem mass spectrometry in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In addition, the antidyskinetic effects of KD5040 on pathological movements triggered by l-dopa were investigated by testing abnormal involuntary movements (AIMs) and measuring the activations of FosB, cAMP-dependent phosphor protein of 32 kDa (DARPP-32), extracellular signal-regulated kinases (ERK), and cAMP response element-binding (CREB) protein in the striatum.ResultsKD5040 synergistically improved the motor function when low-dose l-dopa (LL) was co-administered. In addition, it significantly reversed MPTP-induced lowering of SP, improved ENK levels in the basal ganglia, and ameliorated abnormal reduction in glutamate content in the motor cortex. Furthermore, KD5040 significantly lowered AIMs and controlled abnormal levels of striatal FosB, pDARPP-32, pERK, and pCREB induced by high-dose l-dopa.ConclusionsKD5040 lowered the effective dose of l-dopa and alleviated LID. These findings suggest that KD5040 may be used as an adjunct therapy to enhance the efficacy of l-dopa and alleviate its adverse effects in patients with PD.
Highlights
The dopamine precursor L-3, 4-dihydroxyphenylalanine (L-dopa) remains the gold standard pharmacological therapy for patients with Parkinson’s disease (PD), long-term treatment with this drug has been known to result in several adverse effects, including L-dopa-induced dyskinesia (LID)
Behavioral assessments of the synergistic effects of L-dopa and KD5040 Muscle strength and ability to balance gradually decreased in the MPTP group
Motor function tests revealed that mice treated with MPTP exhibited significantly lower performance from days 13 to 20 after the first MPTP injection compared to the control group (Figs. 2, 3 and 4)
Summary
The dopamine precursor L-3, 4-dihydroxyphenylalanine (L-dopa) remains the gold standard pharmacological therapy for patients with Parkinson’s disease (PD), long-term treatment with this drug has been known to result in several adverse effects, including L-dopa-induced dyskinesia (LID). Parkinson’s disease (PD) is the second most common neurodegenerative disorder It manifests as the deterioration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the subsequent depletion of dopamine in the striatum [1], leading to the well-known motor symptoms associated with PD, including akinesia, resting tremor, bradykinesia, and rigidity [2, 3]. The current treatment approaches for PD are dopamine-centric and typically include L-3,4-dihydroxyphenylalanine (L-dopa), which is a dopamine precursor and/or dopaminergic agonist These approaches have been successful, alternative treatment strategies need to be developed because the long-term use of L-dopa demands progressive dose escalations and inevitably results in various complications, including motor fluctuations referred as L-dopa-induced dyskinesia (LID) [4]. A number of non-dopaminergic treatments have been suggested for PD due to its diversity of symptoms but have produced limited clinical benefits
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