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      Cistanche tubulosa Protects Dopaminergic Neurons through Regulation of Apoptosis and Glial Cell-Derived Neurotrophic Factor: in vivo and in vitro

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          Abstract

          Parkinson’s disease (PD) is a neurodegenerative disease with the pathological hallmark of reduced nigrostriatal dopamine. In traditional Chinese medicine (TCM) clinical practice, the nanopowder of Cistanche tubulosa has therapeutic effects on PD. To identify the therapeutic mechanism, this study tested the protective effect of different doses of MPP +-induced toxicity in MES23.5 cells using the MTT assay and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice (vehicles). Immunohistochemistry was used to assess cytomorphology and tyrosine hydroxylase (TH) expression. Behavioral tests in vehicles, high performance liquid chromatography (HPLC) tests in dopamine, immunohistochemistry and western blot analysis were used to detect the expression of TH, glial cell line-derived neurotrophic factor (GDNF) and its receptors. Our results demonstrated that the C. tubulosa nanopowder improved the viability of MPP +-treated cells, increased TH expression and reduced the number of apoptotic cells. It also increased Bcl2 protein expression and suppressed Bax protein expression in MPP +-treated cells in a dose-dependent manner. In addition, C. tubulosa nanopowder improved the behavioral deficits in vehicle mice, reduced the stationary duration of swimming, enhanced the ability for spontaneous activity and increased the expression of GDNF, the GDNF family receptor alpha (GFRα1) and Ret in cells of the substantia nigra (SN). Furthermore, the protein expression of GDNF, GFRα1 and Ret increased after treatment with different doses of C. tubulosa nanopowder, with a significant difference between the high-dose and vehicle groups. The protein expression of Bcl2 and Bax were similar in the in vivo and in vitro, which suggested that C. tubulosa nanopowder has anti-apoptotic effects in neurons.

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          Parkinson disease: from pathology to molecular disease mechanisms.

          Parkinson disease (PD) is a complex neurodegenerative disorder with both motor and nonmotor symptoms owing to a spreading process of neuronal loss in the brain. At present, only symptomatic treatment exists and nothing can be done to halt the degenerative process, as its cause remains unclear. Risk factors such as aging, genetic susceptibility, and environmental factors all play a role in the onset of the pathogenic process but how these interlink to cause neuronal loss is not known. There have been major advances in the understanding of mechanisms that contribute to nigral dopaminergic cell death, including mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammation. However, it is not known if the same processes are responsible for neuronal loss in nondopaminergic brain regions. Many of the known mechanisms of cell death are mirrored in toxin-based models of PD, but neuronal loss is rapid and not progressive and limited to dopaminergic cells, and drugs that protect against toxin-induced cell death have not translated into neuroprotective therapies in humans. Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have again expanded our knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals. We seem to be missing some key parts of the jigsaw, the trigger event starting many years earlier in the disease process, and what we are looking at now is merely part of a downstream process that is the end stage of neuronal death. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease.

            Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive cell loss confined mostly to dopaminergic neurons of the substantia nigra. Several factors, including oxidative stress, and decreased activity of complex I mitochondrial respiratory chain, are involved in the degenerative process. Yet, the underlying mechanisms leading to dopaminergic cell loss remain elusive. Morphological assessment for different modes of cell death: apoptosis, necrosis or autophagic degeneration, can contribute significantly to the understanding of this neuronal loss. Ultrastructural examination revealed characteristics of apoptosis and autophagic degeneration in melanized neurons of the substantia nigra in PD patients. The results suggest that even at the final stage of the disease, the dopaminergic neurons are undergoing active process of cell death.
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              Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo.

              Glial-cell-line-derived neurotrophic factor (GDNF), a recently cloned new member of the transforming growth factor-beta superfamily, promotes survival of cultured fetal mesencephalic dopamine neurons and is expressed in the developing striatum. There have, however, been no reports about effects of GDNF in situ. We have used the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces parkinsonian symptoms in man, to determine whether GDNF might exert protective or regenerative effects in vivo in the adult nigrostriatal dopamine system in C57/B1 mice. GDNF injected over the substantia nigra or in striatum before MPTP potently protects the dopamine system, as shown by numbers of mesencephalic dopamine nerve cell bodies, dopamine nerve terminal densities and dopamine levels. When GDNF is given after MPTP, dopamine levels and fibre densities are significantly restored. In both cases, motor behaviour is increased above normal levels. We conclude that intracerebral GDNF administration exerts both protective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment strategies for Parkinson's disease.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                16 December 2016
                2016
                : 8
                : 295
                Affiliations
                [1] 1Institute of Integrated Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine Fuzhou, China
                [2] 2Department of Internal Medicine, Xiamen Hai Cang Hospital Xiamen, China
                [3] 3Department of Geratology, Longyan First Hospital Longyan, China
                Author notes

                Edited by: Fernanda Laezza, University of Texas Medical Branch, USA

                Reviewed by: Guo-qing Zheng, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, China; Gang Chen, Nanjing University of Chinese Medicine, China

                *Correspondence: Jing Cai caij1@ 123456163.com

                These authors have contributed equally to this work.

                Article
                10.3389/fnagi.2016.00295
                5159610
                3ae359ed-4380-451f-8e99-da15d727ebd7
                Copyright © 2016 Xu, Fan, Ye, Cong, Qin, Chen and Cai.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 May 2016
                : 21 November 2016
                Page count
                Figures: 9, Tables: 0, Equations: 0, References: 47, Pages: 14, Words: 8792
                Funding
                Funded by: Vanderbilt University 10.13039/100006537
                Categories
                Neuroscience
                Original Research

                Neurosciences
                cistanche tubulosa,parkinson,dopaminergic neurons,apoptosis,gdnf
                Neurosciences
                cistanche tubulosa, parkinson, dopaminergic neurons, apoptosis, gdnf

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