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Title: Masitinib significantly slows disease progression in postparalysis transgenic SOD1 G93A rats and reduced infla...

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Title: Masitinib significantly slows disease progression in postparalysis transgenic SOD1

G93A

rats and

reduced inflammation in both central and peripheral nervous systems Additional authors (in order)

Emiliano Trias 1 Sofía Ibarburu 1 Romina Barreto-Núñez 1 Joël Babdor 2,3,4,5 Thiago T. Maciel 2,3,4,5,6,7 Matthias Guillo 2,3,4,5 Laurent Gros 8 Alain Moussy 8 Colin D. Mansfield 8 Patrice Dubreuil 7,8,9 Pablo Díaz-Amarilla 10 Patricia Cassina 11 Laura Martínez-Palma 1 Ivan C. Moura 2,3,4,5,6,7 Joseph Beckman 12 Olivier Hermine 2,3,4,5,6,7,8,13

Institution name, city, state, country of additional authors: 1

Institut Pasteur de Montevideo, Uruguay

2

Imagine Institute, Hôpital Necker, Paris, France

3

INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France 4

Paris Descartes–Sorbonne Paris Cité University, Imagine Institute, Paris, France

5

CNRS ERL 8254, Paris, France

6

Laboratory of Excellence GR-Ex, Paris, France

7

Equipe Labélisée par la Ligue Nationale contre le cancer, Paris, France

8

AB Science, Paris, France

9

CRCM, [Signaling, Hematopoiesis and Mechanism of Oncogenesis], Inserm,U1068; Institut PaoliCalmettes; Aix-Marseille Univ, UM105; CNRS, UMR7258, Marseille, F-13009, France

10

Laboratorio de Neurobiología Celular y Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay

11

Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

12

Linus Pauling Institute, Department of Biochemistry and Biophysics, Environmental Health Sciences Center, Oregon State University, USA

13

Department of Hematology, Necker Hospital, Paris, France

Abstracts must contain the background, hypothesis, methods, results to date (if ongoing) and discussion/conclusions. Not to Exceed 350 Words. Typed font must be Times New Roman and no smaller than 11 Pt. Do not use continuation pages, tables, or illustrations.

Background Neuroinflammation and microgliosis are major neuropathological features of amyotrophic lateral sclerosis (ALS). In rats expressing the SOD1G93A mutation, the rapid spread of paralysis coincides with the emergence and proliferation of a population of aberrant glial cells that typically surround spinal motor neurons. Previous studies have shown the importance of neuron-derived colony stimulating factor (M-CSF) via its receptor CSF-1R in microglial proliferation. Likewise, activated non-neuronal cells such as microglia, macrophages and mast cells are known to produce a wide array of pro-inflammatory mediators with evidence of their upregulation found in ALS patients. Masitinib is a small molecule drug that selectively inhibits the tyrosine kinases of CSF1R, c-Kit, LYN, FYN, and PDGFR in the nanomolar range. Hypothesis We hypothesized that pharmacologic inhibition of CSF-1/CSF-1R signaling by masitinib treatment might prevent the appearance of aberrant glial cells, regulate inflammation in both central and peripheral nervous systems, and slow paralysis progression. Methods Masitinib (30 mg/kg/day) was orally administered to symptomatic SOD1G93A rats immediately after paralysis onset or 7 days after paralysis onset and compared against matched vehicle-treated control groups. Results Treatment of already paralytic rats with masitinib resulted in an unprecedented increase in post-paralysis survival with respect to controls. Compared with control, masitinib significantly (p