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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 treatment reduced the number of aberrant glial cells in the degenerating spinal cord. a Aberrant glial cells expressing GFAP (green) and S100β (red) in the ventral horn of the spinal cord. Dotted white lines mark the border between white and grey matter in the upper images and outline motor neurons in high magnification panels. In the vehicle-treated rats aberrant glial cells (white arrows) surround motor neurons as compared with asymptomatic (Tg Asympt) where glial cells express low S100β. Masitinib (30 mg/kg/day) prevented the appearance of aberrant glial cells in the degenerating spinal cord after 20 days treatment. The scheme represents the level of spinal cord segments and Rexed laminae VII and IX where aberrant glial cells were counted (scale bars 50 μm in low magnification and 10 μm in high magnification). b Spinal cord culture from masitinib-treated rats compared with vehicle-treated rats. Relatively few cells were obtained from the degenerating spinal cord after masitinib treatment when compared with vehicle-treated animals (scale bar 15 μm). All data are expressed as mean ± SEM *p < 0.01
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Fig3: Masitinib treatment reduced the number of aberrant glial cells in the degenerating spinal cord. a Aberrant glial cells expressing GFAP (green) and S100β (red) in the ventral horn of the spinal cord. Dotted white lines mark the border between white and grey matter in the upper images and outline motor neurons in high magnification panels. In the vehicle-treated rats aberrant glial cells (white arrows) surround motor neurons as compared with asymptomatic (Tg Asympt) where glial cells express low S100β. Masitinib (30 mg/kg/day) prevented the appearance of aberrant glial cells in the degenerating spinal cord after 20 days treatment. The scheme represents the level of spinal cord segments and Rexed laminae VII and IX where aberrant glial cells were counted (scale bars 50 μm in low magnification and 10 μm in high magnification). b Spinal cord culture from masitinib-treated rats compared with vehicle-treated rats. Relatively few cells were obtained from the degenerating spinal cord after masitinib treatment when compared with vehicle-treated animals (scale bar 15 μm). All data are expressed as mean ± SEM *p < 0.01

Mentions: We then explored whether chronic treatment with masitinib could reduce the number of aberrant glial cells in the degenerating spinal cord, which were identifiable as large GFAP/S100β-positive cells located around motor neurons as described previously [4]. Rats were orally treated with masitinib (30 mg/kg/day), starting right after paralysis onset and during the next 20 days, corresponding to the average post-paralysis survival in untreated rats (Fig. 5). Only rats that initiated paralysis in the hind limbs were used in the experiments in order to reduce experimental variables. As compared with rats treated with vehicle, masitinib significantly reduced the number of aberrant glial cells in the lumbar spinal cord by 40 % (Fig. 3a).Fig. 3


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 treatment reduced the number of aberrant glial cells in the degenerating spinal cord. a Aberrant glial cells expressing GFAP (green) and S100β (red) in the ventral horn of the spinal cord. Dotted white lines mark the border between white and grey matter in the upper images and outline motor neurons in high magnification panels. In the vehicle-treated rats aberrant glial cells (white arrows) surround motor neurons as compared with asymptomatic (Tg Asympt) where glial cells express low S100β. Masitinib (30 mg/kg/day) prevented the appearance of aberrant glial cells in the degenerating spinal cord after 20 days treatment. The scheme represents the level of spinal cord segments and Rexed laminae VII and IX where aberrant glial cells were counted (scale bars 50 μm in low magnification and 10 μm in high magnification). b Spinal cord culture from masitinib-treated rats compared with vehicle-treated rats. Relatively few cells were obtained from the degenerating spinal cord after masitinib treatment when compared with vehicle-treated animals (scale bar 15 μm). All data are expressed as mean ± SEM *p < 0.01
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Masitinib treatment reduced the number of aberrant glial cells in the degenerating spinal cord. a Aberrant glial cells expressing GFAP (green) and S100β (red) in the ventral horn of the spinal cord. Dotted white lines mark the border between white and grey matter in the upper images and outline motor neurons in high magnification panels. In the vehicle-treated rats aberrant glial cells (white arrows) surround motor neurons as compared with asymptomatic (Tg Asympt) where glial cells express low S100β. Masitinib (30 mg/kg/day) prevented the appearance of aberrant glial cells in the degenerating spinal cord after 20 days treatment. The scheme represents the level of spinal cord segments and Rexed laminae VII and IX where aberrant glial cells were counted (scale bars 50 μm in low magnification and 10 μm in high magnification). b Spinal cord culture from masitinib-treated rats compared with vehicle-treated rats. Relatively few cells were obtained from the degenerating spinal cord after masitinib treatment when compared with vehicle-treated animals (scale bar 15 μm). All data are expressed as mean ± SEM *p < 0.01
Mentions: We then explored whether chronic treatment with masitinib could reduce the number of aberrant glial cells in the degenerating spinal cord, which were identifiable as large GFAP/S100β-positive cells located around motor neurons as described previously [4]. Rats were orally treated with masitinib (30 mg/kg/day), starting right after paralysis onset and during the next 20 days, corresponding to the average post-paralysis survival in untreated rats (Fig. 5). Only rats that initiated paralysis in the hind limbs were used in the experiments in order to reduce experimental variables. As compared with rats treated with vehicle, masitinib significantly reduced the number of aberrant glial cells in the lumbar spinal cord by 40 % (Fig. 3a).Fig. 3

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