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

Trias E, Ibarburu S, Barreto-Núñez R, Babdor J, Maciel TT, Guillo M, Gros L, Dubreuil P, Díaz-Amarilla P, Cassina P, Martínez-Palma L, Moura IC, Beckman JS, Hermine O, Barbeito L - J Neuroinflammation (2016)

Bottom Line: Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown.We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations.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.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay.

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.

No MeSH data available.


Related in: MedlinePlus

Masitinib ameliorates microgliosis and motor neuron pathology. a Microglia marker Iba1 confocal images. Note the significant reduction of microglial cells in masitinib-treated rat spinal cords when compared with vehicle-treated ones. High magnification panels show a significant reduction in the number of microglial cells that surround motor neurons after masitinib chronic treatment (scale bars 50 μm low magnification and 20 μm high magnification). b Confocal image of ChAT in the lumbar spinal cord (dotted line) indicates the border between white and grey matter (scale bar 50 μm). The graph below to the left represents the quantitative analysis showing the number of motor neurons in the ventral horn in each condition. The graph to the right represents the quantitation of the motor neuron soma diameter showing the decreased diameter of surviving motor neurons in vehicle-treated rats and the protective effect of masitinib (insets in a) (scale bar 10 μm). All data are expressed as mean ± SEM *p < 0.01, **p < 0.01
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4940876&req=5

Fig4: Masitinib ameliorates microgliosis and motor neuron pathology. a Microglia marker Iba1 confocal images. Note the significant reduction of microglial cells in masitinib-treated rat spinal cords when compared with vehicle-treated ones. High magnification panels show a significant reduction in the number of microglial cells that surround motor neurons after masitinib chronic treatment (scale bars 50 μm low magnification and 20 μm high magnification). b Confocal image of ChAT in the lumbar spinal cord (dotted line) indicates the border between white and grey matter (scale bar 50 μm). The graph below to the left represents the quantitative analysis showing the number of motor neurons in the ventral horn in each condition. The graph to the right represents the quantitation of the motor neuron soma diameter showing the decreased diameter of surviving motor neurons in vehicle-treated rats and the protective effect of masitinib (insets in a) (scale bar 10 μm). All data are expressed as mean ± SEM *p < 0.01, **p < 0.01

Mentions: Post-paralysis masitinib treatment also significantly reduced microgliosis as assessed by the number of cells expressing Iba1+, CD206+, or CD68+ cells in the ventral horn of the lumbar spinal cord, when compared with vehicle-treated animals (Fig. 4a, see Additional file 1: Figure S1A). Remarkably, there was a reduction of hypertrophic Iba1+ microglia cells surrounding motor neurons at thoracic and cervical levels of the degenerating spinal cords, suggesting that masitinib may prevented the spread of neuroinflammation along the neuraxis (see Additional file 1: Figure S1B).Fig. 4


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

Trias E, Ibarburu S, Barreto-Núñez R, Babdor J, Maciel TT, Guillo M, Gros L, Dubreuil P, Díaz-Amarilla P, Cassina P, Martínez-Palma L, Moura IC, Beckman JS, Hermine O, Barbeito L - J Neuroinflammation (2016)

Masitinib ameliorates microgliosis and motor neuron pathology. a Microglia marker Iba1 confocal images. Note the significant reduction of microglial cells in masitinib-treated rat spinal cords when compared with vehicle-treated ones. High magnification panels show a significant reduction in the number of microglial cells that surround motor neurons after masitinib chronic treatment (scale bars 50 μm low magnification and 20 μm high magnification). b Confocal image of ChAT in the lumbar spinal cord (dotted line) indicates the border between white and grey matter (scale bar 50 μm). The graph below to the left represents the quantitative analysis showing the number of motor neurons in the ventral horn in each condition. The graph to the right represents the quantitation of the motor neuron soma diameter showing the decreased diameter of surviving motor neurons in vehicle-treated rats and the protective effect of masitinib (insets in a) (scale bar 10 μm). All data are expressed as mean ± SEM *p < 0.01, **p < 0.01
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940876&req=5

Fig4: Masitinib ameliorates microgliosis and motor neuron pathology. a Microglia marker Iba1 confocal images. Note the significant reduction of microglial cells in masitinib-treated rat spinal cords when compared with vehicle-treated ones. High magnification panels show a significant reduction in the number of microglial cells that surround motor neurons after masitinib chronic treatment (scale bars 50 μm low magnification and 20 μm high magnification). b Confocal image of ChAT in the lumbar spinal cord (dotted line) indicates the border between white and grey matter (scale bar 50 μm). The graph below to the left represents the quantitative analysis showing the number of motor neurons in the ventral horn in each condition. The graph to the right represents the quantitation of the motor neuron soma diameter showing the decreased diameter of surviving motor neurons in vehicle-treated rats and the protective effect of masitinib (insets in a) (scale bar 10 μm). All data are expressed as mean ± SEM *p < 0.01, **p < 0.01
Mentions: Post-paralysis masitinib treatment also significantly reduced microgliosis as assessed by the number of cells expressing Iba1+, CD206+, or CD68+ cells in the ventral horn of the lumbar spinal cord, when compared with vehicle-treated animals (Fig. 4a, see Additional file 1: Figure S1A). Remarkably, there was a reduction of hypertrophic Iba1+ microglia cells surrounding motor neurons at thoracic and cervical levels of the degenerating spinal cords, suggesting that masitinib may prevented the spread of neuroinflammation along the neuraxis (see Additional file 1: Figure S1B).Fig. 4

Bottom Line: Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown.We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations.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.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay.

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.

No MeSH data available.


Related in: MedlinePlus