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      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

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      Effect of Tianqi antitremor granules on behavioral manifestations and expression of G protein-coupled receptor kinase 6 and β-arrestin1 in levodopa-induced dyskinesia in a rat model of Parkinson’s disease

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          Abstract

          Background

          Recent studies have shown that expression of G protein-coupled receptor kinase 6 (GRK6) and β-arrestin1 in the striatum is closely associated with hyperactive dopamine receptors in rats with levodopa-induced dyskinesia (LID). Our research group has shown that Tianqi antitremor granules have a significant effect on the motor complications of Parkinson’s disease (PD). However, whether Tianqi antitremor granules have an effect on the behavioral manifestations and expression of GRK6 and β-arrestin1 in rats with LID is unknown.

          Methods

          Rats with PD received twice daily intraperitoneal injections of levodopa for 4 weeks to induce dyskinesia. Rats with LID were randomly divided into five groups: an LID-control group, an LID group, a levodopa plus Tianqi antitremor granules as traditional Chinese medicine (TCM)-low group, a levodopa plus TCM-medium group, and levodopa plus TCM-high group. Peak intensity of rotations was measured. GRK6 and β-arrestin1 expression in the striatum of the dyskinetic rats was observed by immunohistochemistry and Western blotting.

          Results

          Pulsatile treatment with levodopa induced abnormal involuntary movements in rats with PD similar to LID in patients with PD. We found that repeated levodopa administration increased peak rotations in dyskinetic rats. However, peak rotations were decreased in rats given levodopa plus the different doses of Tianqi antitremor granules. In accordance with changed behavior, GRK6 and β-arrestin1 expression was decreased in rats with PD and was persistently low in rats with LID, but this decrease was prevented by coadministration of levodopa and Tianqi antitremor granules.

          Conclusion

          Tianqi antitremor granules ameliorated levodopa-induced dyskinetic behavior, reversed the decrease in GRK6 and β-arrestin1 expression, and acted as a useful adjunctive medicine for the treatment of LID.

          Most cited references24

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          Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway.

          Ronald Deumens, Arjan Blokland, Jos Prickaerts (2002)
          Human idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by degeneration of the dopaminergic neurons of the nigrostriatal pathway. Different 6-OHDA rat models of PD have been developed in which this toxin has been injected into different parts of the nigrostriatal pathway: (a) the medial forebrain bundle which leads to extensive dopamine (DA) depletion; (b) the substantia nigra pars compacta, which leads to more specific and moderate DA depletions; and (c) subregions of the caudate-putamen complex (CPu), which also leads to specific DA depletions. In this article we review the dopaminergic depletion and behavioral consequences of 6-OHDA lesions in the rat. It was examined whether the relation between DA depletion and behavioral deficits mimic idiopathic PD. In addition, it was evaluated which model most closely approximates the human situation, especially in relation to the stage of this progressive disease. It was concluded that with respect to the site of the lesion, rats with partial lesions of the ventrolateral CPu are the most appropriate models to study early and late stages of PD. The choice of the behavioral parameters determines the use of unilateral or bilateral lesions, although it is obvious that the bilateral model mimics the human situation more closely. (c) 2002 Elsevier Science (USA).
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            G protein-coupled receptor kinases: more than just kinases and not only for GPCRs.

            John Tesmer, Arcady R Mushegian, Arcady Mushegian (2012)
            G protein-coupled receptor (GPCR) kinases (GRKs) are best known for their role in homologous desensitization of GPCRs. GRKs phosphorylate activated receptors and promote high affinity binding of arrestins, which precludes G protein coupling. GRKs have a multidomain structure, with the kinase domain inserted into a loop of a regulator of G protein signaling homology domain. Unlike many other kinases, GRKs do not need to be phosphorylated in their activation loop to achieve an activated state. Instead, they are directly activated by docking with active GPCRs. In this manner they are able to selectively phosphorylate Ser/Thr residues on only the activated form of the receptor, unlike related kinases such as protein kinase A. GRKs also phosphorylate a variety of non-GPCR substrates and regulate several signaling pathways via direct interactions with other proteins in a phosphorylation-independent manner. Multiple GRK subtypes are present in virtually every animal cell, with the highest expression levels found in neurons, with their extensive and complex signal regulation. Insufficient or excessive GRK activity was implicated in a variety of human disorders, ranging from heart failure to depression to Parkinson's disease. As key regulators of GPCR-dependent and -independent signaling pathways, GRKs are emerging drug targets and promising molecular tools for therapy. Targeted modulation of expression and/or of activity of several GRK isoforms for therapeutic purposes was recently validated in cardiac disorders and Parkinson's disease. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Beta-arrestins and cell signaling.

              Seungkirl Ahn, Scott DeWire, Robert Lefkowitz … (2007)
              Upon their discovery, beta-arrestins 1 and 2 were named for their capacity to sterically hinder the G protein coupling of agonist-activated seven-transmembrane receptors, ultimately resulting in receptor desensitization. Surprisingly, recent evidence shows that beta-arrestins can also function to activate signaling cascades independently of G protein activation. By serving as multiprotein scaffolds, the beta-arrestins bring elements of specific signaling pathways into close proximity. beta-Arrestin regulation has been demonstrated for an ever-increasing number of signaling molecules, including the mitogen-activated protein kinases ERK, JNK, and p38 as well as Akt, PI3 kinase, and RhoA. In addition, investigators are discovering new roles for beta-arrestins in nuclear functions. Here, we review the signaling capacities of these versatile adapter molecules and discuss the possible implications for cellular processes such as chemotaxis and apoptosis.
              Article 0 comments Cited 139 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Title: Drug Design, Development and Therapy
                Publisher: Dove Medical Press
                ISSN (Electronic): 1177-8881
                Publication date Collection: 2013
                Publication date (Electronic): 10 December 2013
                Volume: 7
                Pages: 1481-1489
                Affiliations
                [1 ]Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, People’s Republic of China
                [2 ]Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
                Author notes
                Correspondence: Zhenguo Liu, Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, People’s Republic of China, Tel +86 21 2507 7501, Fax +86 21 2507 7501, Email zhenguoliu2011@ 123456aliyun.com
                Article
                Publisher ID: dddt-7-1481
                DOI: 10.2147/DDDT.S48488
                PMC ID: 3864941
                PubMed ID: 24376341
                SO-VID: 7888164d-4be1-499f-9543-b2ed31a05280
                Copyright © © 2013 Wu et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License
                License:

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: parkinson’s disease,dyskinesia,g protein-coupled receptor kinase 6,traditional chinese medicine,herbal granules,β-arrestin1
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: parkinson’s disease, dyskinesia, g protein-coupled receptor kinase 6, traditional chinese medicine, herbal granules, β-arrestin1

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