title: Chronic administration of AMD3100 increases survival and alleviates pathology in SOD1(G93A) mice model of ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease, involving both upper and lower motor neurons. The disease is induced by multifactorial pathologies, and as such, it requires a multifaceted therapeutic approach. CXCR4, a chemokine receptor widely expressed in neurons and glial cells and its ligand, CXCL12, also known as stromal-cell-derived factor (SDF1), modulate both neuronal function and apoptosis by glutamate release signaling as well as hematopoietic stem and progenitor cells (HSPCs) migration into the blood and their homing towards injured sites. Inhibition approaches towards the CXCR4/CXCL12 signaling may result in preventing neuronal apoptosis and alter the HSPCs migration and homing. Such inhibition can be achieved by means of treatment with AMD3100, an antagonist of the chemokine receptor CXCR4.
  
  
  
  We chronically treated male and female transgenic mice model of ALS, SOD1(G93A) mice, with AMD3100. Mice body weight and motor function, evaluated by Rotarod test, were recorded once a week. The most effective treatment regimen was repeated for biochemical and histological analyses in female mice.
  
  
  
  We found that chronic administration of AMD3100 to SOD1(G93A) mice led to significant extension in mice lifespan and improved motor function and weight loss. In addition, the treatment significantly improved microglial pathology and decreased proinflammatory cytokines in spinal cords of treated female mice. Furthermore, AMD3100 treatment decreased blood-spinal cord barrier (BSCB) permeability by increasing tight junction proteins levels and increased the motor neurons count in the lamina X area of the spinal cord, where adult stem cells are formed.
  
  
  
  These data, relevant to the corresponding disease mechanism in human ALS, suggest that blocking CXCR4 by the small molecule, AMD3100, may provide a novel candidate for ALS therapy with an increased safety.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978, Tel Aviv, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Rabinovich-Nikitin
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978, Tel Aviv, Israel.
authors.forename: Assaf
authors.initials: A
authors.lastname: Ezra
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978, Tel Aviv, Israel.
authors.forename: Beka
authors.initials: B
authors.lastname: Barbiro
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978, Tel Aviv, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Rabinovich-Toidman
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978, Tel Aviv, Israel. beka@post.tau.ac.il.
authors.forename: Beka
authors.initials: B
authors.lastname: Solomon
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001596:Benzylamines; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D062507:Claudin-5 / Q000378:metabolism; D000080027:Cyclams; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000473:pathology; D053580:Muscle Strength / Q000187:drug effects / Q000235:genetics; D011596:Psychomotor Disorders / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D002135:Calcium-Binding Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D062507:Claudin-5; D000080027:Cyclams; D016207:Cytokines; D006571:Heterocyclic Compounds; D008840:Microfilament Proteins; D019718:Receptors, CXCR4; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C088327:plerixafor
keywords: ALS; AMD3100; Blood-spinal cord barrier; CXCR4/CXCL12; Hematopoietic stem and progenitor cells; Microglia; SOD1G93A mice