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

 

Autor(es):
Trias, Emiliano ; Ibarburu, Sofía ; Barreto-Núñez, Romina ; Babdor, Joël ; Maciel, Thiago T. ; Guillo, Matthias ; Gros, Laurent ; Dubreuil, Patrice ; Díaz-Amarilla, Pablo ; Cassina, Patricia ; Martínez-Palma, Laura ; Moura, Ivan C. ; Beckman, Joseph S. ; Hermine, Olivier ; Barbeito, Luis
Tipo:
Artículo
Versión:
Publicado
Financiadores:
Agencia Nacional de Investigación e Innovación
Resumen:

Background: In the SOD1G93A 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 SOD1G93A 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 SOD1G93A spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1G93A 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.

Año:
2016
Idioma:
Inglés
Temas:
ALS
Aberrant glial cells
Neurodegeneration
Masitinib
M-CSF
Ciencias Médicas y de la Salud
Biotecnología de la Salud
Institución:
Institut Pasteur de Montevideo
Repositorio:
REDI-IPMON
Enlace(s):
http://hdl.handle.net/20.500.12381/169
http://dx.doi.org/10.1186/s12974-016-0620-9
Nivel de acceso:
Acceso abierto