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J Neuroinflammation. 2016 Jul 11;13(1):177. doi: 10.1186/s12974-016-0620-9.

Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis.

Trias E1, Ibarburu S1, Barreto-Núñez R1, Babdor J2,3,4,5, Maciel TT2,3,4,5,6,7, Guillo M2,3,4,5, Gros L8, Dubreuil P7,8,9, Díaz-Amarilla P10, Cassina P11, Martínez-Palma L11, Moura IC2,3,4,5,6,7, Beckman JS12, Hermine O13,14,15,16,17,18,19,20,21, Barbeito L22.

Author information

1
Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay.
2
Imagine Institute, Hôpital Necker, 24 boulevard du Montparnasse, 75015, 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, Cedex, France.
8
AB Science, 3 Avenue Georges V, 75008, Paris, France.
9
CRCM, [Signaling, Hematopoiesis and Mechanism of Oncogenesis], Inserm, U1068, Institut Paoli-Calmettes, 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, Corvallis, USA.
13
Imagine Institute, Hôpital Necker, 24 boulevard du Montparnasse, 75015, Paris, France. ohermine@gmail.com.
14
INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France. ohermine@gmail.com.
15
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. ohermine@gmail.com.
16
CNRS ERL 8254, Paris, France. ohermine@gmail.com.
17
Laboratory of Excellence GR-Ex, Paris, France. ohermine@gmail.com.
18
Equipe Labélisée par la Ligue Nationale contre le cancer, Paris, Cedex, France. ohermine@gmail.com.
19
AB Science, 3 Avenue Georges V, 75008, Paris, France. ohermine@gmail.com.
20
Department of Hematology, Necker Hospital, Paris, France. ohermine@gmail.com.
21
Centre national de référence des mastocytoses (CEREMAST), Paris, France. ohermine@gmail.com.
22
Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay. barbeito@pateur.edu.uy.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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 %.

CONCLUSIONS:

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.

KEYWORDS:

ALS; Aberrant glial cells; M-CSF; Masitinib; Neurodegeneration

PMID:
27400786
PMCID:
PMC4940876
DOI:
10.1186/s12974-016-0620-9
[Indexed for MEDLINE]
Free PMC Article

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