Acupuncture Alleviates Levodopa-Induced Dyskinesia via Melanin-Concentrating Hormone in Pitx3-Deficient aphakia and 6-Hydroxydopamine-Lesioned Mice.

Although L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the most effective medication for treating Parkinson's disease (PD) motor symptoms, its prolonged administration causes several adverse effects, including dyskinesia. To identify the mechanisms underlying the effects of acupuncture on L-DOPA-induced dyskinesia (LID), antidyskinetic effects of acupuncture were investigated in two mouse models of PD. Acupuncture stimulation at GB34 alleviated abnormal involuntary movements (AIMs) in Pitx3-deficient aphakia mice (ak/ak) following L-DOPA administration and these effects were reproduced in 6-hydroxydopamine (6-OHDA)-lesioned mice with LID. A transcriptome analysis of the hypothalamus revealed pro-melanin-concentrating hormone (Pmch) gene was highly expressed in acupuncture-treated mouse from ak/ak model of LID as well as 6-OHDA model of LID. Acupuncture combined with the administration of MCH receptor antagonist did not have any beneficial effects on dyskinesia in L-DOPA-injected ak/ak mice, but the intranasal administration of MCH attenuated LID to the same degree as acupuncture in both ak/ak and 6-OHDA mice with LID. A gene expression profile with a hierarchical clustering analysis of the dyskinesia-induced ak/ak mouse brain revealed an association between the mechanisms underlying acupuncture and MCH. Additionally, altered striatal responses to L-DOPA injection were observed after prolonged acupuncture and MCH treatments, which suggests that these treatment modalities influenced the compensatory mechanisms of LID. In summary, present study demonstrated that acupuncture decreased LID via hypothalamic MCH using L-DOPA-administered ak/ak and 6-OHDA mouse models and that MCH administration resulted in novel antidyskinetic effects in these models. Thus, acupuncture and MCH might be valuable therapeutic candidates for PD patients suffering from LID.

Effects of a combination treatment of KD5040 and L-dopa in a mouse model of Parkinson's disease.

BACKGROUND: Although 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. METHODS: The 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. RESULTS: KD5040 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. CONCLUSIONS: KD5040 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.

Novel Neuroprotective Effects of Melanin-Concentrating Hormone in Parkinson's Disease.

Acupuncture has shown the therapeutic effect on various neurodegenerative disorders including Parkinson's disease (PD). While investigating the neuroprotective mechanism of acupuncture, we firstly found the novel function of melanin-concentrating hormone (MCH) as a potent neuroprotective candidate. Here, we explored whether hypothalamic MCH mediates the neuroprotective action of acupuncture. In addition, we aimed at evaluating the neuroprotective effects of MCH and elucidating underlying mechanism in vitro and in vivo PD models. First, we tested whether hypothalamic MCH mediates the neuroprotective effects of acupuncture by challenging MCH-R1 antagonist (i.p.) in mice PD model. We also investigated whether MCH has a beneficial role in dopaminergic neuronal protection in vitro primary midbrain and human neuronal cultures and in vivo MPTP-induced, Pitx3-/-, and A53T mutant mice PD models. Transcriptomics followed by quantitative PCR and western blot analyses were performed to reveal the neuroprotective mechanism of MCH. We first found that hypothalamic MCH biosynthesis was directly activated by acupuncture treatment and that administration of an MCH-R1 antagonist reverses the neuroprotective effects of acupuncture. A novel finding is that MCH showed a beneficial role in dopaminergic neuron protection via downstream pathways related to neuronal survival. This is the first study to suggest the novel neuroprotective action of MCH as well as the involvement of hypothalamic MCH in the acupuncture effects in PD, which holds great promise for the application of MCH in the therapy of neurodegenerative diseases.

p53 signalling mediates acupuncture-induced neuroprotection in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a selective loss of dopamine (DA) neurons in the substantia nigra of the midbrain. Recently, it has been demonstrated that acupuncture treatment has protective effects in PD. However, to date, the molecular mechanisms underlying acupuncture's effect on DA neuronal protection are largely unknown. In this study, we report that p53 signalling mediates the protective effects of acupuncture treatment in a mouse model of PD. We found that the acupuncture treatment in the mouse PD model results in significant recovery to the normal in the context of behaviour and molecular signatures. We found that the gene network associated with p53 signalling is closely involved in the protective effects of acupuncture treatment in PD. Consistent with this idea, we demonstrated that specific knockout of the p53 gene in the midbrain DA neurons abrogates the acupuncture induced protective effects in the mouse model of PD. Thus, these data suggest that p53 signalling mediates the protective effects of acupuncture treatment in PD.

Gastrodia elata Blume alleviates L-DOPA-induced dyskinesia by normalizing FosB and ERK activation in a 6-OHDA-lesioned Parkinson's disease mouse model.

BACKGROUND: Gastrodia elata Blume (GEB), commonly used medicinal herb, has been reported as a promising candidate for neurodegenerative diseases such as Parkinson's disease. The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is the gold-standard drug for Parkinson's disease, but long-term treatment results in the L-dopa-induced dyskinesia (LID). This study was undertaken to examine the beneficial effects of GEB on L-DOPA induced dyskinesia in 6-hydroxydopamine (6-OHDA)-induced experimental Parkinsonism. METHODS: We tested the effects of GEB on LID in 6-hydroxydopamine hydrochloride-hemiparkinsonian mice. To analyze the dyskinetic anomalies, we measured abnormal involuntary movement (AIM). Immunohistological analyses of pERK and FosB expressions in the striatum are performed to explore the mechanism of GEB on LID. RESULTS: The finding of this study demonstrated that GEB (200, 400 and 800 mg/kg) alleviated L-dopa induced AIMs in a dose-dependent manner. In each integrative AIM subtype analysis, we also found that the GEB (400 and 800 mg/kg) treatment decreased L-DOPA-induced axial, limb, orolingual, and locomotive AIMs compared to the LID group. In addition, GEB normalized the abnormal LID-induced increase of pERK1/2 and FosB, the immediate early genes of LID in the striatum. CONCLUSIONS: In conclusion, our results provide a novel insight into the pharmacological actions of GEB that could have a benefit for PD patients through the reduction of LID.