title: Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis.
abstract: In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.
  
  
  
  The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1(G93A) rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset.
  
  
  
  We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1(G93A) spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1(G93A) rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %.
  
  
  
  These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.
authors.affiliation: Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Trias
authors.affiliation: Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay.
authors.forename: Sofía
authors.initials: S
authors.lastname: Ibarburu
authors.affiliation: Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay.
authors.forename: Romina
authors.initials: R
authors.lastname: Barreto-Núñez
authors.affiliation: Imagine Institute, Hôpital Necker, 24 boulevard du Montparnasse, 75015, Paris, France.|INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.|CNRS ERL 8254, Paris, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Babdor
authors.affiliation: Imagine Institute, Hôpital Necker, 24 boulevard du Montparnasse, 75015, Paris, France.|INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.|CNRS ERL 8254, Paris, France.|Laboratory of Excellence GR-Ex, Paris, France.|Equipe Labélisée par la Ligue Nationale contre le cancer, Paris, Cedex, France.
authors.forename: Thiago T
authors.initials: TT
authors.lastname: Maciel
authors.affiliation: Imagine Institute, Hôpital Necker, 24 boulevard du Montparnasse, 75015, Paris, France.|INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.|CNRS ERL 8254, Paris, France.
authors.forename: Matthias
authors.initials: M
authors.lastname: Guillo
authors.affiliation: AB Science, 3 Avenue Georges V, 75008, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gros
authors.affiliation: Equipe Labélisée par la Ligue Nationale contre le cancer, Paris, Cedex, France.|AB Science, 3 Avenue Georges V, 75008, Paris, France.|CRCM, [Signaling, Hematopoiesis and Mechanism of Oncogenesis], Inserm, U1068, Institut Paoli-Calmettes, Aix-Marseille Univ, UM105, CNRS, UMR7258, Marseille, F-13009, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.affiliation: Laboratorio de Neurobiología Celular y Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
authors.forename: Pablo
authors.initials: P
authors.lastname: Díaz-Amarilla
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Patricia
authors.initials: P
authors.lastname: Cassina
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Laura
authors.initials: L
authors.lastname: Martínez-Palma
authors.affiliation: Imagine Institute, Hôpital Necker, 24 boulevard du Montparnasse, 75015, Paris, France.|INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.|CNRS ERL 8254, Paris, France.|Laboratory of Excellence GR-Ex, Paris, France.|Equipe Labélisée par la Ligue Nationale contre le cancer, Paris, Cedex, France.
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Moura
authors.affiliation: Linus Pauling Institute, Department of Biochemistry and Biophysics, Environmental Health Sciences Center, Oregon State University, Corvallis, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Beckman
authors.affiliation: Imagine Institute, Hôpital Necker, 24 boulevard du Montparnasse, 75015, Paris, France. ohermine@gmail.com.|INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France. ohermine@gmail.com.|Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. ohermine@gmail.com.|CNRS ERL 8254, Paris, France. ohermine@gmail.com.|Laboratory of Excellence GR-Ex, Paris, France. ohermine@gmail.com.|Equipe Labélisée par la Ligue Nationale contre le cancer, Paris, Cedex, France. ohermine@gmail.com.|AB Science, 3 Avenue Georges V, 75008, Paris, France. ohermine@gmail.com.|Department of Hematology, Necker Hospital, Paris, France. ohermine@gmail.com.|Centre national de référence des mastocytoses (CEREMAST), Paris, France. ohermine@gmail.com.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay. barbeito@pateur.edu.uy.
authors.forename: Luis
authors.initials: L
authors.lastname: Barbeito
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000235:genetics / Q000401:mortality; D000818:Animals; D001549:Benzamides; D016923:Cell Death; D004195:Disease Models, Animal; D018450:Disease Progression; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology*; D006801:Humans; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D010243:Paralysis / Q000188:drug therapy* / Q000209:etiology*; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines; D051381:Rats; D055647:Rats, Transgenic; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D013844:Thiazoles / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013844:Thiazoles; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C526575:masitinib
keywords: ALS; Aberrant glial cells; M-CSF; Masitinib; Neurodegeneration