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      Neuroprotection in Parkinson’s disease: facts and hopes

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          Abstract

          Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Behind the symptoms there is a complex pathological mechanism which leads to a dopaminergic cell loss in the substantia nigra pars compacta. Despite the strong efforts, curative treatment has not been found yet. To prevent a further cell death, numerous molecules were tested in terms of neuroprotection in preclinical (in vitro, in vivo) and in clinical studies as well. The aim of this review article is to summarize our knowledge about the extensively tested neuroprotective agents (Search period: 1991–2019). We detail the underlying pathological mechanism and summarize the most important results of the completed animal and clinical trials. Although many positive results have been reported in the literature, there is still no evidence that any of them should be used in clinical practice (Cochrane analysis was performed). Therefore, further studies are needed to better understand the pathomechanism of PD and to find the optimal neuroprotective agent(s).

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          Most cited references105

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          Kynurenines in the CNS: recent advances and new questions.

          Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntington's disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value.
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            Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease.

            (1993)
            In 1987 we began a multicenter controlled clinical trial of deprenyl (a monoamine oxidase inhibitor) and tocopherol (a component of vitamin E that traps free radicals) in the treatment of early Parkinson's disease. We randomly assigned 800 patients to one of four treatments: placebo, active tocopherol and deprenyl placebo, active deprenyl and tocopherol placebo, or both active drugs. The primary end point was the onset of disability prompting the clinical decision to begin administering levodopa. An interim analysis showed that deprenyl was beneficial (N Engl J Med 1989;321:1364-71). We report the results of tocopherol treatment after a mean (+/- SD) follow-up of 14 +/- 6 months, as well as the follow-up results for deprenyl. There was no beneficial effect of tocopherol or any interaction between tocopherol and deprenyl. The beneficial effects of deprenyl, which occurred largely during the first 12 months of treatment, remained strong and significantly delayed the onset of disability requiring levodopa therapy (hazard ratio, 0.50; 95 percent confidence interval, 0.41 to 0.62; P < 0.001). The difference in the estimated median time to the end point was about nine months. The ratings for Parkinson's disease improved during the first three months of deprenyl treatment; the motor performance of deprenyl-treated patients worsened after the treatments were withdrawn. Deprenyl (10 mg per day) but not tocopherol (2000 IU per day) delays the onset of disability associated with early, otherwise untreated Parkinson's disease. The action of deprenyl that accounts for its beneficial effects remains unclear.
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              Toxin-induced models of Parkinson's disease.

              Parkinson's disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. It results mainly from the death of dopaminergic neurons in the substantia nigra. PD etiology remains mysterious, whereas its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. Most insights into PD pathogenesis come from investigations performed in experimental models of PD, especially those produced by neurotoxins. Although a host of natural and synthetic molecules do exert deleterious effects on dopaminergic neurons, only a handful are used in living laboratory animals to recapitulate some of the hallmarks of PD. In this review, we discuss what we believe are the four most popular parkinsonian neurotoxins, namely 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. The main goal is to provide an updated summary of the main characteristics of each of these four neurotoxins. However, we also try to provide the reader with an idea about the various strengths and the weaknesses of these neurotoxic models.
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                Author and article information

                Contributors
                vecsei.laszlo@med.u-szeged.hu
                Journal
                J Neural Transm (Vienna)
                J Neural Transm (Vienna)
                Journal of Neural Transmission
                Springer Vienna (Vienna )
                0300-9564
                1435-1463
                11 December 2019
                11 December 2019
                2020
                : 127
                : 5
                : 821-829
                Affiliations
                [1 ]GRID grid.9008.1, ISNI 0000 0001 1016 9625, Department of Neurology, Faculty of Medicine, Interdisciplinary Excellence Centre, Albert Szent-Györgyi Clinical Center, , University of Szeged, ; Semmelweis u. 6., Szeged, 6725 Hungary
                [2 ]MTA-SZTE Neuroscience Research Group, Szeged, Hungary
                Author information
                http://orcid.org/0000-0001-8037-3672
                Article
                2115
                10.1007/s00702-019-02115-8
                7242234
                31828513
                8a627e7a-4a5e-40d9-b09e-f174f1f2a216
                © The Author(s) 2019

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 October 2019
                : 3 December 2019
                Funding
                Funded by: GINOP-2.3.2-15- 2016-00034
                Award ID: GINOP-2.3.2-15- 2016-00034
                Award Recipient :
                Funded by: EFOP-3.6.1-16-2016-00008
                Award ID: EFOP-3.6.1-16-2016-00008
                Award Recipient :
                Funded by: Ministry of Human Capacities, Hungary
                Award ID: 20391-3/2018/FEKUSTRAT
                Award Recipient :
                Funded by: Hungarian Brain Research Program
                Award ID: 2017-1.2.1-NKP-2017-00002 NAP VI/4
                Award Recipient :
                Categories
                Neurology and Preclinical Neurological Studies - Review Article
                Custom metadata
                © Springer-Verlag GmbH Austria, part of Springer Nature 2020

                neuroprotection,parkinson’s disease,animal models,clinical trials,pathomechanism

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