og:image: http://www.jneurosci.org/sites/default/files/highwire/jneuro/39/19.cover-source.jpg citation_mjid: jneuro;39/19/3752 article:published_time: 2019-05-08 og:site_name: Journal of Neuroscience citation_reference: citation_journal_title=J Cell Physiol;citation_author=SA. Acosta;citation_author=N. Tajiri;citation_author=I. de la Pena;citation_author=M. Bastawrous;citation_author=PR. Sanberg;citation_author=Y. Kaneko;citation_author=CV. Borlongan;citation_title=Alpha-synuclein as a pathological link between chronic traumatic brain injury and Parkinson's disease;citation_pages=1024-1032;citation_volume=230;citation_year=2015;citation_pmid=25251017;citation_doi=10.1002/jcp.24830 citation_journal_title: Journal of Neuroscience type: article og:description: Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease. Parkinson's disease is a movement disorder with characteristic motor features that arise due to the loss of dopaminergic neurons from the substantia nigra. Although symptomatic treatment by the dopamine precursor levodopa and dopamine agonists can improve motor symptoms, no disease-modifying therapy exists yet. Here, we show that Emapunil (AC-5216, XBD-173), a synthetic ligand of the translocator protein 18, ameliorates degeneration of dopaminergic neurons, preserves striatal dopamine metabolism, and prevents motor dysfunction in female mice treated with the MPTP, as a model of parkinsonism. We found that Emapunil modulates the inositol requiring kinase 1? (IRE ?)/X-box binding protein 1 (XBP1) unfolded protein response pathway and induces a shift from pro-inflammatory toward anti-inflammatory microglia activation. Previously, Emapunil was shown to cross the blood?brain barrier and to be safe and well tolerated in a Phase II clinical trial. Therefore, our data suggest that Emapunil may be a promising approach in the treatment of Parkinson's disease. SIGNIFICANCE STATEMENT Our study reveals a beneficial effect of Emapunil on dopaminergic neuron survival, dopamine metabolism, and motor phenotype in the MPTP mouse model of parkinsonism. In addition, our work uncovers molecular networks which mediate neuroprotective effects of Emapunil, including microglial activation state and unfolded protein response pathways. These findings not only contribute to our understanding of biological mechanisms of translocator protein 18 (TSPO) function but also indicate that translocator protein 18 may be a promising therapeutic target. We thus propose to further validate Emapunil in other Parkinson's disease mouse models and subsequently in clinical trials to treat Parkinson's disease. citation_issn: 0270-6474 citation_full_html_url: http://www.jneurosci.org/content/39/19/3752.full citation_public_url: http://www.jneurosci.org/content/39/19/3752 dc:title: Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism | Journal of Neuroscience Content-Encoding: UTF-8 citation_pdf_url: http://www.jneurosci.org/content/jneuro/39/19/3752.full.pdf citation_section: Research Articles citation_lastpage: 3769 citation_journal_abbrev: J. Neurosci. DC.Identifier: 10.1523/JNEUROSCI.2070-18.2019 DC.Rights: Copyright © 2019 the authors citation_author: Jing Gong citation_abstract_html_url: http://www.jneurosci.org/content/39/19/3752.abstract citation_issue: 19 HW.identifier: /jneuro/39/19/3752.atom citation_doi: 10.1523/JNEUROSCI.2070-18.2019 citation_volume: 39 Content-Language: en Generator: Drupal 7 (http://drupal.org) citation_author_orcid: https://orcid.org/0000-0002-2575-3899 DC.AccessRights: restricted citation_publication_date: 2019/05/08 citation_title: Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism citation_author_institution: 1German Center for Neurodegenerative Diseases, 53127 Bonn, Germany, citation_publisher: Society for Neuroscience citation_id: 39/19/3752 title: Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism | Journal of Neuroscience DC.Description: Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease. Parkinson's disease is a movement disorder with characteristic motor features that arise due to the loss of dopaminergic neurons from the substantia nigra. Although symptomatic treatment by the dopamine precursor levodopa and dopamine agonists can improve motor symptoms, no disease-modifying therapy exists yet. Here, we show that Emapunil (AC-5216, XBD-173), a synthetic ligand of the translocator protein 18, ameliorates degeneration of dopaminergic neurons, preserves striatal dopamine metabolism, and prevents motor dysfunction in female mice treated with the MPTP, as a model of parkinsonism. We found that Emapunil modulates the inositol requiring kinase 1? (IRE ?)/X-box binding protein 1 (XBP1) unfolded protein response pathway and induces a shift from pro-inflammatory toward anti-inflammatory microglia activation. Previously, Emapunil was shown to cross the blood?brain barrier and to be safe and well tolerated in a Phase II clinical trial. Therefore, our data suggest that Emapunil may be a promising approach in the treatment of Parkinson's disease. SIGNIFICANCE STATEMENT Our study reveals a beneficial effect of Emapunil on dopaminergic neuron survival, dopamine metabolism, and motor phenotype in the MPTP mouse model of parkinsonism. In addition, our work uncovers molecular networks which mediate neuroprotective effects of Emapunil, including microglial activation state and unfolded protein response pathways. These findings not only contribute to our understanding of biological mechanisms of translocator protein 18 (TSPO) function but also indicate that translocator protein 18 may be a promising therapeutic target. We thus propose to further validate Emapunil in other Parkinson's disease mouse models and subsequently in clinical trials to treat Parkinson's disease. Content-Type-Hint: text/html; charset=utf-8 DC.Format: text/html DC.Publisher: Society for Neuroscience DC.Contributor: Jing Gong Content-Type: application/xhtml+xml; charset=UTF-8 X-Parsed-By: org.apache.tika.parser.DefaultParser og:type: article article:section: Research Articles citation_pmid: 30796158 citation_article_type: Research Article og:title: Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism citation_abstract:

Parkinson9s disease is the second most common neurodegenerative disease, after Alzheimer9s disease. Parkinson9s disease is a movement disorder with characteristic motor features that arise due to the loss of dopaminergic neurons from the substantia nigra. Although symptomatic treatment by the dopamine precursor levodopa and dopamine agonists can improve motor symptoms, no disease-modifying therapy exists yet. Here, we show that Emapunil (AC-5216, XBD-173), a synthetic ligand of the translocator protein 18, ameliorates degeneration of dopaminergic neurons, preserves striatal dopamine metabolism, and prevents motor dysfunction in female mice treated with the MPTP, as a model of parkinsonism. We found that Emapunil modulates the inositol requiring kinase 1? (IRE ?)/X-box binding protein 1 (XBP1) unfolded protein response pathway and induces a shift from pro-inflammatory toward anti-inflammatory microglia activation. Previously, Emapunil was shown to cross the blood?brain barrier and to be safe and well tolerated in a Phase II clinical trial. Therefore, our data suggest that Emapunil may be a promising approach in the treatment of Parkinson9s disease.

SIGNIFICANCE STATEMENT Our study reveals a beneficial effect of Emapunil on dopaminergic neuron survival, dopamine metabolism, and motor phenotype in the MPTP mouse model of parkinsonism. In addition, our work uncovers molecular networks which mediate neuroprotective effects of Emapunil, including microglial activation state and unfolded protein response pathways. These findings not only contribute to our understanding of biological mechanisms of translocator protein 18 (TSPO) function but also indicate that translocator protein 18 may be a promising therapeutic target. We thus propose to further validate Emapunil in other Parkinson9s disease mouse models and subsequently in clinical trials to treat Parkinson9s disease.

DC.Title: Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism issue_cover_image: http://www.jneurosci.org/sites/default/files/highwire/jneuro/39/19.cover-source.jpg citation_firstpage: 3752 viewport: width=device-width, initial-scale=1, maximum-scale=3, minimum-scale=1, user-scalable=yes HW.pisa: jneuro;39/19/3752 DC.Language: en DC.Date: 2019-05-08 category: research-article og:url: http://www.jneurosci.org/content/39/19/3752