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      Neurotoxin-Induced Animal Models of Parkinson Disease: Pathogenic Mechanism and Assessment

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          Abstract

          Parkinson disease (PD) is the second most common neurodegenerative movement disorder. Pharmacological animal models are invaluable tools to study the pathological mechanisms of PD. Currently, invertebrate and vertebrate animal models have been developed by using several main neurotoxins, such as 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, paraquat, and rotenone. These models achieve to some extent to reproduce the key features of PD, including motor defects, progressive loss of dopaminergic neurons in substantia nigra pars compacta, and the formation of Lewy bodies. In this review, we will highlight the pathogenic mechanisms of those neurotoxins and summarize different neurotoxic animal models with the hope to help researchers choose among them accurately and to promote the development of modeling PD.

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          Most cited references97

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          Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease.

          Alzheimer disease (AD) and Parkinson disease (PD) are the two most common age-related neurodegenerative diseases characterized by prominent neurodegeneration in selective neural systems. Although a small fraction of AD and PD cases exhibit evidence of heritability, among which many genes have been identified, the majority are sporadic without known causes. Molecular mechanisms underlying neurodegeneration and pathogenesis of these diseases remain elusive. Convincing evidence demonstrates oxidative stress as a prominent feature in AD and PD and links oxidative stress to the development of neuronal death and neural dysfunction, which suggests a key pathogenic role for oxidative stress in both AD and PD. Notably, mitochondrial dysfunction is also a prominent feature in these diseases, which is likely to be of critical importance in the genesis and amplification of reactive oxygen species and the pathophysiology of these diseases. In this review, we focus on changes in mitochondrial DNA and mitochondrial dynamics, two aspects critical to the maintenance of mitochondrial homeostasis and function, in relationship with oxidative stress in the pathogenesis of AD and PD. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis.

            Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.
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              A highly reproducible rotenone model of Parkinson's disease.

              The systemic rotenone model of Parkinson's disease (PD) accurately replicates many aspects of the pathology of human PD and has provided insights into the pathogenesis of PD. The major limitation of the rotenone model has been its variability, both in terms of the percentage of animals that develop a clear-cut nigrostriatal lesion and the extent of that lesion. The goal here was to develop an improved and highly reproducible rotenone model of PD. In these studies, male Lewis rats in three age groups (3, 7 or 12-14 months) were administered rotenone (2.75 or 3.0 mg/kg/day) in a specialized vehicle by daily intraperitoneal injection. All rotenone-treated animals developed bradykinesia, postural instability, and/or rigidity, which were reversed by apomorphine, consistent with a lesion of the nigrostriatal dopamine system. Animals were sacrificed when the PD phenotype became debilitating. Rotenone treatment caused a 45% loss of tyrosine hydroxylase-positive substantia nigra neurons and a commensurate loss of striatal dopamine. Additionally, in rotenone-treated animals, alpha-synuclein and poly-ubiquitin positive aggregates were observed in dopamine neurons of the substantia nigra. In summary, this version of the rotenone model is highly reproducible and may provide an excellent tool to test new neuroprotective strategies.
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                Author and article information

                Journal
                ASN Neuro
                ASN Neuro
                ASN
                spasn
                ASN NEURO
                SAGE Publications (Sage CA: Los Angeles, CA )
                1759-0914
                29 May 2018
                Jan-Dec 2018
                : 10
                : 1759091418777438
                Affiliations
                [1 ]College of Life Sciences, Institute for Conservation and Utilization of Agro-Bioresources in Dabie Mountains, Xinyang Normal University, China
                Author notes
                [*]Jin-Jing Jia, College of Life Sciences, Institute for Conservation and Utilization of Agro-Bioresources in Dabie Mountains, Xinyang Normal University, Xinyang, China. Email: jiajinjing1986@ 123456126.com
                Article
                10.1177_1759091418777438
                10.1177/1759091418777438
                5977437
                29809058
                5a39287d-e820-4847-9125-45924d8a5d40
                © The Author(s) 2018

                Creative Commons CC-BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License ( http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 11 February 2018
                : 12 April 2018
                Funding
                Funded by: National Natural Science Foundation of China, FundRef https://doi.org/10.13039/501100001809;
                Award ID: 31600837
                Categories
                Review
                Custom metadata
                January-December 2018

                Neurosciences
                parkinson disease,neurotoxins,animal models,pathogenic mechanism,assessment
                Neurosciences
                parkinson disease, neurotoxins, animal models, pathogenic mechanism, assessment

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